MXPA06003190A - Benzimidazole derivates:preparation and pharmaceutical applications - Google Patents

Abstract

The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to benzimidazole containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with dysregulation of histone deacetylase (HDAC).

Description

BENCIMIDAZOLE DERIVATIVES: PREPARATION AND PHARMACEUTICAL APPLICATIONS FIELD OF THE INVENTION The present invention relates to hydroxamate compounds that are inhibitors of histone deacetylase. More particularly, the present invention relates to benzimidazole-containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders, in addition to other diseases that include, relate to or are associated with the dysregulation of histone deacetylase (HDAC).

BACKGROUND OF THE INVENTION In general, the architecture of local chromatin is recognized as an important factor in the regulation of gene expression. The architecture of chromatin, a protein-DNA complex, is strongly influenced by the post-translational modifications of the histones that are the protein components. The reversible acetylation of histones is a key component in the regulation of gene expression, by altering the accessibility of transcription factors to DNA. In general, increased levels of histone acetylation are associated with higher transcription activity, while decreased levels of acetylation are associated with the repression of gene expression [Wadem P. A. Hum. Mol. Genet 10. 693-698 (2001), De Ruijter A.J.M. et al., Biochem. L, 370. 737-749 (2003)]. In normal cells, histone deacetylases (HDAC) and histone acetyltransferase together control the level of acetylation of histones to maintain balance. By inhibition of HDAC, the accumulation of acetylated histones occurs, which causes diverse cellular responses dependent on the cell type, such as apoptosis, necrosis, differentiation, cell survival, inhibition of proliferation and cytostasis. HDAC inhibitors have been studied for their therapeutic effects on cancer cells. For example, suberoylanilidohydroxamic acid (SAHA) is a powerful inducer of differentiation and / or apoptosis in murine erythroleukemia, bladder and myeloma cell lines [Richon V. M. et al., Proc. Nati Acad. Sci. USA, 93: 5705-5708 (1996), Richon V. M. et al., Proc. Nati Acad. Sci. USA, 95: 3003-3007 (1998)]. It has been shown that SAHA suppresses the growth of prostate cancer cells in vitro and in vivo [Butler L. M. et al, Cancer Res. 60. 5165-5170 (2000)]. Other HDAC inhibitors widely studied for their anticancer activities include trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. Biol. Chem., 265, 17174 (1990), Kijima M. et al, J. Biol. Chem., 268, 22429 (1993)]. Trichostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, due to the in vivo instability of these compounds, they have less interest as anticancer drugs. Recently, other small HDAC inhibitor molecules have been made available for clinical evaluation [US 6,552,065]. Other HDAC inhibitor compounds have been reported in the literature [Bouchain G. et al, J. Med. Chem., 46 , 820-830 (2003)] and in patents [WO 03/066579A2, WO 01/38322 Al]. The in vivo activity of said inhibitors can be directly monitored by their ability to increase the amount of acetylated histones in the biological sample. It has been reported that HDAC inhibitors interfere with neurodegenerative processes, for example, inhibitors of HDAC slow down the polyglutamine-dependent neurodegeneration [Nature, 413 (6857): 739 ^ 3, October 18, 2001]. In addition, it is known that HDAC inhibitors inhibit the production of cytokines such as TNF, IFN, IL-1, which are known to be involved in inflammatory diseases and / or disorders of the immune system. [J. Biol. Chem. 1990; 265 (18): 10230-10237; Science, 1998; 281: 1001-1005; Dinarello C. A. and Moldawer L. L. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis. A first for clinicians. 2nd Edition, Amergen Inc., 2000]. However, it is still necessary to provide other HDAC inhibitors, which can be expected to have useful and improved pharmaceutical properties, such as anticancer agents.

SUMMARY OF THE INVENTION In one aspect, the present invention provides compounds of the formula (I): wherein Rl is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, arylheteroalkyl, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy , amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or male Substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl , heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino , sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; or Rl = L; R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, - N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) OR5, -SH, -SR6 , -OR6 and acyl; or R2 = L; R3 is selected from the group consisting of H, Cl-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6, acyl and -NR 7 R 8; R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R5 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R6 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-Ll-W- wherein Cy is C 1 -C 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or several substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, Arylamino, sulfonyl, alkylsulfonyl,. arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl. Ll is selected from the group consisting of Cl -C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (0) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; b) L = Cy-Ll-W-L2 wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected in a manner independent of the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; Ll and L2 are the same or different and independently are C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -0CF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0 -N (R10) -; c) L = Cy- (CH2 ) mW- wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkyls ulphonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; m is O. 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -K (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; d) L = L1-W-L2 Ll and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; R9 and RIO are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and acyl; Z is a single bond or is selected from -CH2-, -CH2CH2-, -CH = CH- and C3-C6 cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl; or one of its pharmaceutically acceptable salts. An appropriate genus of hydroxamic compounds are those of the formula la: Formula wherein R 1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN , -N02, - CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy , heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, - C (0) OR 5, - COR5, -SH, -SR6, -OR6 and acyl; or Rl = L; R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, - N02, -CF3, -0CF3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy , aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR 5, -C (0) OR 5, -SH, - SR6, -OR6 and acyl; or R2 = L; R3 is selected from the group consisting of: H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH -C (0) OR5, -COR5, -SH, -SR6, -0R6, acyl and-NR7R8; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R7 and R8 is independently selected from the group composed of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-Ll-W- wherein Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy, or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl , heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl , arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl. Ll is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9> -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; b) L = Cy- Ll-W-L2 wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, the chylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR5, -COR5, -SH, -SR6, -OR6 and acyl; Ll and L2 are the same or different and independently C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -OCF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) -N (R10) -; c) L = Cy- (CH2) mW-wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected in a manner independent of the group consisting of halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl , hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl , aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; m is O. 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) -N (R10) -; d) L = L1-W-L2 Ll and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; R9 and RIO are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl; Z is a single bond or is selected from -CH2-, -CH2CH2-, -CH = CH-, C3-C6 cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl; or one of its pharmaceutically acceptable salts. Another group of useful compounds are those of the formula Ib: Formula Ib wherein R 1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN , -N02, -CF3, -0CF3, alkyl, alkenyl, alkyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR5, -SH, -SR6, -OR6 and acyl; or Rl = L; R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, - N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) OR5, -SH, -SR6 , -OR6 and acyl; or R2-L; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfnyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (0) OR 5, -COR 5, -SH, -SR 6, acyl and -NR 7 R 8; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-Ll-W- wherein Cy is C 1 -C 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or several substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl , arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -io C (0) OR5, -COR5, -SH, -SR6, -OR6 and cilo Ll is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; alkyl, alkoxy, 5-acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (0) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; 0 b) L = Cy-Ll-W-L2 wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more selected substituents independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,. heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR 5, -COR 5, -SH, - SR6, -OR6 and acyl; Ll and L2 are the same or different and are, independently, C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -0CF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S- -S (0) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) - -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0> -N (R10) -; c) L = Cy- (CH2 ) mW- wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl; each of which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl , haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl , arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl, m is 0. 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) -N (R10) -; d) L = L1-W-L2 Ll and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -0CF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (0) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; R9 and RIO are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl; Z is a single bond or is selected from -CH2-, -CH2CH2-, -CH = CH-, C3-C6 cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl; or one of its pharmaceutically acceptable salts. As with any group of structurally related compounds possessing a particular utility, certain groups are preferred for the compounds of formulas (I), (la) and (Ib) in their end-use application. In certain preferred embodiments, R1 is selected from the group consisting of C1-C10 alkyl. alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl and heteroarylalkyl, each of which may be substituted as set forth above. In another embodiment, it is preferred that R1 is selected from the group consisting of H, hydroxyalkyl, alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aminoalkyl, and heterocycloalkyl, each of which may be substituted as set forth above. In another embodiment, it is preferred that R1 is selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl, each of which may be substituted as set forth above. In another embodiment, it is preferred that, if R 1 is alkyl or heteroalkyl, then it is not substituted with a cycloalkyl, aryl, heteroaryl or heterocycloalkyl. Particularly preferred values of Rl are: H; methyl; (pyridin-2-yl) methyl; (pyridin-3-yl) methyl; ethyl; 2-hydroxy-ethyl; 2- (pyridin-2-yl) ethyl; 2- (pyridin-3-yl) ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2- (morpholin-4-yl) -ethyl; 2- (piperidin-1-yl) -ethyl; 2- (pütolidin-1-yl) -ethyl; 2-diethylamino-ethyl; propyl; 2,3-di-hydroxy-propyl; 3-hydroxypropyl; 3-methoxypropyl; 3-isopropoxy-propyl; 2,2-dimethylpropyl; 3-dimethylamino-propyl; 3-dimethylamino-2,2-dimethyl-propyl; 3- (2-oxo-pyrrolidin-1-yl) -propyl; 3- (morpholin-4-yl) -propyl; 3- (imadazol-1-yl) -propyl; 3- (4-methyl-piperidin-1-yl) -propyl; 3- (pyrrolidin-1-yl) -propyl; 4-dimethylamino-butyl; 5-hydroxy-pentyl; allyl; benzyl; and 3,4,5-trimethoxybenzyl. In certain preferred embodiments, R 2 is selected from the group consisting of H, halogen, C 1 -C 10 alkyl. alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl and heteroarylalkyl, each of which may be substituted as set forth above. In another embodiment, it is preferred that R2 be selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, 5-cycloalkyl, and L, each of which may be substituted as set forth above. In another embodiment, it is preferred that R2 be selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl, each of which may be substituted as previously established. In another embodiment, it is preferred that, if R 2 is alkyl or heteroalkyl, then it is not substituted with a cycloalkyl, aryl, heteroaryl or heterocycloalkyl. Particularly preferred values of R2 are: H; methyl; benzylamino-15 methyl; dibenzylamino-methyl; [2- (4-fluoro-phenyl) -acetylamino] -methyl; [2- (4-methoxy-phenyl) -acetylamino] -methyl; 4-methoxy-benzylamino-methyl; benzyloxy-methyl; phenylacetylamino-methyl; l-amino-2-phenyl-ethyl; 2- benzylamino-ethyl; 2- (3-methoxy-phenyl) -ethyl; 2- (pyridin-3-yl) ethyl; 2- (2-phenoxyacetylamino) -ethyl; 2-benzenesulfonylamino-ethyl; 2-phenyl-ethyl; 0 isopropyl; 2-phenylpropyl; 3-phenylpropyl; 3-phenoxy-propyl; 3- (1H-indol-3-yl) -propyl; 4-methoxy phenyl; 4-fluoro-phenyl; 4-benzyloxy-3-methoxy-phenyl; isobutyl; cyclohexyl; octyl; benzyl; ? iridin-2-yl; pyridin-4-yl; thiophen-3-yl; benzylsulfanyl and 2-phenylmethanesulfonyl. If R1 or R2 are substituted, substituents of particular preference are selected from the group consisting of: halogen, = 0, = S, -CN, -N02, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (0) OR 5, COOH, SH and acyl. X and Y can be the same or different and are preferably H, halogen, C1-C4 alkyl, -CF3, -N02, -C (0) R5, -OR6, -SR6, -CN and NR7R8. X is, most preferably, H; And it is, most preferably, H; X and Y are, most preferably, in positions 4 and 7 of the aromatic ring. R 3 is preferably H, C 1 -C 6 alkyl or acyl, more preferably H or C 1 -C 4 alkyl, most preferably H; R 4 is, preferably, H or C 1 -C 4 alkyl, most preferably R 5 is, preferably, C 1 -C 4 alkyl, heteroalkyl or acyl, most preferably methyl; R 6 is, preferably, C 1 -C 4 alkyl, heteroalkyl or acyl, most preferably C 1 -C 4 alkyl; R7 and R8 are preferably selected from the group consisting of H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl. The remainder Z is preferably a group of the formula -CH = CH- The remainder is preferably in the "E" configuration and is preferably in the 5 or 6 position, most preferably in the position 5. In addition to the compounds of formula I, the described embodiments also refer to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites of said compounds and pharmaceutically acceptable salts of said metabolites. Taken together, said compounds, salts, prodrugs and metabolites are sometimes referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors". The invention also relates to pharmaceutical compositions that include a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient. In still another aspect of the present invention, there is provided a method for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis, including the administration of a therapeutically effective amount of a compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (la), more preferably a compound of the formula (Ib), as described herein. Preferably, the disorder of the group consisting of, without limitation, cancer, inflammatory diseases / disorders of the immune system, angiofibroma, cardiovascular diseases (eg, restenosis, arteriosclerosis), fibrotic diseases (eg, liver fibrosis), diabetes, is selected. autoimmune diseases, acute and chronic neurodegenerative diseases such as nervous tissue disorders, Huntington's disease and infectious diseases such as fungal, bacterial and viral infections. In another embodiment, the disorder is a proliferatiyo disorder. Preferably, the proliferative disorder is cancer. The invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis, including a compound of the formula (I) as described herein. Preferably, the agent is an anti-cancer agent. Preferably, the agent contains a compound of the formula (la), more preferably a compound of the formula (Ib). The invention also relates to the use of compounds of the formula (I) in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis. Preferably, the disorder is a proliferative disorder, more preferably cancer. Surprisingly, the compounds of the present invention show low toxicity, together with a powerful antiproliferative activity.

In still another embodiment of the invention there is provided a method for the treatment of a disorder, disease or condition that can be treated by inhibiting histone deacetylase, even by administering a therapeutically effective amount of a compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (la), more preferably a compound of the formula (Ib), as described herein.

Preferably, the disorder is selected from the group formed, without limitations, by antiproliferative disorders (e.g., cancers); neurodegenerative diseases such as Huntington's disease, polyglutamine disease, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear palsy, torsional dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles de la Tourette syndrome, diffuse Lewy body disease, progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage , primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome; metabolic diseases including type 2 diabetes; degenerative diseases of the eye, including glaucoma, macular degeneration associated with age, rubella glaucoma; inflammatory disease and / or immune system disorders, including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes, Sjoegren's syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; disease including angiogenesis, for example cancer, psoriasis, rheumatoid arthritis; psychological disorders that include bipolar illness, schizophrenia, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example by Candida Albicans, bacterial infections, viral infections, for example herpes simplex, protozoal infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis, and hematopoietic disorders such as , for example thalassemia, anemia and sickle cell anemia. The invention also provides agents for the treatment of a disorder, a disease or a pathological condition that can be treated by inhibiting histone deacetylase, which includes a compound of the formula (I), as described herein. Preferably, the agent is an anti-cancer agent. The invention also relates to the use of compounds of the formula (I) in the preparation of a medicament for the treatment of a disorder, a disease or a pathological condition that can be treated by inhibition of histone deacetylase. The invention also provides a method for inhibiting cell proliferation that includes the administration of an effective amount of a compound according to formula (I). In still another aspect of the invention there is provided a method of treating a neurodegenerative disorder in a patient, which includes the administration of a therapeutically effective amount of a compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (la), more preferably a compound of the formula (Ib), as described herein. Preferably, the neurodegenerative disorder is Huntington's disease. The invention also provides agents for the treatment of a neurodegenerative disorder that includes a compound of the formula (I) as described herein. Preferably, the agent is an agent against Huntington's disease. The invention also relates to the use of compounds of the formula (I) in the preparation of a medicament for the treatment of a neurodegenerative disorder. Preferably, the neurodegenerative disorder is Huntington's disease. In yet another aspect, the invention provides a method of treating an inflammatory disease and / or immune system disorder in a patient, including administering to a patient a therapeutically effective amount of xm compound of the formula (I). Preferably, the method includes the administration of a compound of the formula (la), more preferably a compound of the formula (Ib), as described herein. In one embodiment, the inflammatory disease and / or disorder of the immune system is rheumatoid arthritis. In another embodiment, the inflammatory disease and / or immune system disorder is systemic lupus erythematosus. The invention also provides agents for the treatment of an inflammatory disease and / or immune system disorder including a compound of the formula (I), as described herein. The invention also relates to the use of compounds of the formula (I) in the preparation of a medicament for the treatment of an inflammatory disease and / or disorder of the immune system. In an embodiment, the inflammatory disease and / or the immune system disorder is rheumatoid arthritis. In another embodiment, the inflammatory disease and / or the immune system disorder is systemic lupus erythematosus. To monitor the efficacy of said compounds, the invention describes a suitable method for detecting and quantifying acetylated histone levels in samples of human or animal species such as tumor tissue, encephalon and blood. The method is based on an enzyme-linked immunosorbent assay (ELISA) and can be used for the quantification of acetylated histones in extracts or cell samples of human or animal species such as tumor tissue, encephalon and blood. Preferably over conventional systems, the ELISA allows high yields, quantitative determinations of the concentration of acetylated histones as a measure of the efficacy of pharmacological treatments or of the potency of the drug in the respective biological test system. For a general review of conventional ELISA techniques, refer to Crowther JR (1995) ELISA theory and practice in Method in molecular biology vol. 42, Human. In yet another aspect, the invention provides a method for measuring the concentration of acetylated histone in a biological sample by an enzyme-linked immunosorbent assay, wherein the enzyme-linked immunosorbent assay includes a combination of a primary capture antibody, a thereof, and a secondary detection antibody, or a portion thereof. Preferably, the primary capture antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, xm acetylated anti-H3 polyclonal antibody, a polyclonal goat anti-H3 antibody, an acetylated goat polyclonal anti-H3 antibody and combinations thereof. Preferably, the secondary detection antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, an acetylated anti-H3 polyclonal antibody, a polyclonal goat anti-H3 antibody, a goat acetylated polyclonal anti-H3 antibody and corresponding thereof. In a particularly preferred embodiment, the primary capture antibody is a mouse anti-H3 monoclonal antibody and the secondary detection antibody is a rat acetylated anti-H3 polyclonal antibody. The invention also provides a method for identifying the pharmacological effect of a histone deacetylase inhibitor in a cell, wherein the method includes the steps of: a) providing a cell that has been treated with a histone deacetylase inhibitor; b) measuring the concentration of acetylated histone in the cell by a method according to any of claims 32 to 35; and c) comparing the concentration of acetylated histone with the acetylated histone concentration of a control sample. In a preferred embodiment, the control sample is derived from a cell that has not been treated with a histone deacetylase inhibitor. In another preferred embodiment, the cell is a tumor cell. Preferably, the histone deacetylase inhibitor includes a compound of the formula (1). The invention also provides a method for identifying the pharmacological effect of a histone deacetylase inhibitor in a subject, wherein the method includes the steps of: a) obtaining a biological sample from a subject that has been treated with a histone deacetylase inhibitor; b) measuring the concentration of acetylated histone in the biological sample by a method according to the invention as described above; and c) comparing the concentration of acetylated histone with the acetylated histone concentration of a control sample. Preferably, the control sample is a biological sample derived from a subject that has not been treated with a histone deacetylase inhibitor. Preferably, in the methods of the invention, the biological sample is selected from the group consisting of tissue, blood, serum, plasma, urine, saliva and the corresponding combinations.

DETAILED DESCRIPTION OF THE INVENTION Hydroxamate compounds, for example benzimidazoles containing hydroxamic acid, are described in one of the substituents, which may be deacetylase inhibitors including, without limitation, the histone deacetylase inhibitors. The hydroxamate compounds may be suitable for the prevention or treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis when used alone or together with a pharmaceutically acceptable carrier, diluent or excipient. An example of such a disorder is cancer. As used herein, the term "cancer" is a general term intended to encompass the vast number of conditions that are characterized by abnormal uncontrolled growth of cells. It is envisioned that the compounds of the invention will be useful for the treatment of various cancers including, without limitation, bone cancers, for example Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain tumors and CNS tumors, eg, acoustic neuroma, neuroblastomas, glioma and other brain tumors, spinal cord tumors, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasm, gastrointestinal cancers such as stomach cancer, esophageal cancer, small bowel cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer, genitourinary cancers such as testicular cancer, cancer of the penis, cancer of p rhestatic, gynecological cancers such as cervical cancer, ovarian cancer, vaginal cancer, uterine / endometrial cancer, vulvar cancer, gestational trophoblastic cancer, fallopian tube cancer, uterine sarcoma, head and neck cancers that include cancer of the oral cavity, lip cancer, salivary gland cancer, laryngeal cancer,. hypopharyngeal cancer, oropharyngeal cancer, nasal cancer, paranasal cancer, nasopharynx cancer, leukemias such as childhood leukemia, acute lymphocytic leukemia, acute myeloid leukemia , chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, acute promyelocytic leukemia, plasma cell leukemia, myelomas, hematological disorders such as myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstrom's macroglobulinemia, lung cancers such as small cell lung cancer, cancer non-small cell lung, lymphomas such as Hodgkin's disease, non-Hodgkin's lymphoma, cutaneous cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma, eye cancers such as retinoblastoma, intraocular melanoma, skin cancers such as melanoma , non-melanoma skin cancer, Merkel cell cancer, soft tissue sarcoma such as soft tissue sarcoma of childhood, adult soft tissue sarcoma, Kaposi's sarcoma, urinary system cancers such as kidney cancer, tumor of the Wilms, bladder cancer, urethral cancer and transitional cell cancer. Preferably, cancers that can be treated by the compounds of the present invention are breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, stomach cancer and brain cancer. . Preferably, cancers that can be treated by the compounds of the present inventions are cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Preferably, cancers that can be treated by the compounds of the present invention include solid tumors and haematological malignancies. The compounds can also be used for the treatment of a disorder that includes, refers to or is associated with the dysregulation of histone deacetylase (HDAC). Numerous disorders have been implicated with or known to be mediated at least in part by HDAC activity, where it is known that HDAC activity plays an important role in the initiation of the disease, or whose symptoms are known or have been shown to be alleviated by HDAC inhibitors. It is envisioned that disorders of this type capable of being treated by these compounds of the invention include the following, without limitations: antiproliferative disorders (e.g., cancers); neurodegenerative diseases such as Huntington's disease, polyglutamine disease, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles de la Tourette syndrome, diffuse disease of Lewy body, progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy syndrome Drager; metabolic diseases such as type 2 diabetes; degenerative diseases of the eye such as glaucoma, macular degeneration associated with age, rubella glaucoma; inflammatory diseases and / or disorders of the immune system such as rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes, Sjoegren's syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; disease that includes angiogenesis such as cancer, psoriasis, rheumatoid arthritis; psychological disorders such as bipolar illness, schizophrenia, mania, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example by Candida Albicans, bacterial infections, viral infections, such as herpes simplex, protozoal infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis and hematopoietic disorders such as thalassemia, anemia and sickle cell anemia. The hydroxamate compounds of the present invention have the following structure (I): Formula I wherein R 1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, arylheteroalkyl, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted by one or more substituents s selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; or Rl = L; R2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, Heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy , aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, -O, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl , cycloalkyl, cycloalk enyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) OR5, -SH, -SR6, -OR6 and acyl; or R2 = L; R3 is selected from the group consisting of H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (0) OR 5, -COR 5, -SH, -SR 6, acyl and -NR 7 R 8; R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-Ll-W- wherein Cy is C 1 -C 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or several substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, - C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl. Ll is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (0) -, -45 (0) 2-, -N (R9) -, -C (0) N (R9) - S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; b) L = Cy-Ll-W-L2 wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected in a manner independent of the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR6, -COR5, -SH, -SR6, -OR6 and acyl; Ll and L2 are the same or different and are, independently, C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -0CF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) --S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0 > -N (R10) -; c) L = Cy- ( CH2) mW-wherein Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl each of which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen , = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy , alk? xialquilo, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alk ilsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR6, -COR5, -SH, -SR6, -OR6 and acyl; m is O. 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0> - N (R10) -; d) L = L1-W- L2 Ll and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0> - N (R10) -; R9 and RIO are equal or and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and acyl; Z is a single bond or is selected from -CH2- , -CH2CH2-, - CH = CH-, C3-C6 cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. the present term, the unsubstituted term means that there are no substituents or that the only substituents are hydrogen. "Halogen" represents chlorine, fluorine, bromine or iodine. "Alkyl" as a group or part of a group refers to a linear aliphatic hydrocarbon group or branched, preferably a C1-C14 alkyl, co n greater preference C1-C10 alkyl. most preferably, C1-C6, unless otherwise indicated. Examples of suitable linear and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl and the like. "Alkylamino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" means a group -NH-alkyl, "dialkylamino" means a group -N (alkyl) 2, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. "Arylamino" includes both mono-arylamino and di-arylamino, unless specified. Mono-arylamino means a group of the formula aryl-NH-di-arylamino means a group of the formula (aryl2) N-, where the aryl is as defined herein.

"Acyl" means an alkyl-CO- group, wherein the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a C1-C6 alkyl group. "Alkenyl" as a group or part of a group implies an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be linear or branched, preferably with 2-14 carbon atoms, more preferably 2-12 carbon atoms. carbon, most preferably 2-6 carbon atoms, in the chain. The group may contain a plurality of double bonds in the normal chain and the orientation with respect to them is, independently, E or Z. The example alkenyl group includes, but is not limited to, ethenyl and propenyl. "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Preferably, the alkoxy is a Cl-C6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy. "Alkenyloxy" refers to an -O-alkenyl group, wherein the alkenyl is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups. "Alkynyloxy" refers to an -O-alkynyl group, wherein the alkynyl is as defined herein. Preferred alkynyloxy groups are C1-C6 alkynyloxy groups. "Alkoxycarbonyl" refers to a -C (0) -0-alkyl group, wherein alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. "Alkylsulfinyl" means a group -S (0) -alkyl, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but without limitation, methylsulfinyl and ethylsulfinyl. "Alkylsulfonyl" refers to a -S (0) 2 -alkyl group, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to methylsulfonyl and ethylsulfonyl. "Alkynyl as a group or part of a group" means an aliphatic hydrocarbon group containing a triple carbon-carbon bond and which may be linear or branched, preferably with 2-14 carbon atoms, more preferably 2-12 carbon atoms in the chain, preferably 2-6 carbon atoms in the chain. Exemplary structures include, but are not limited to, ethinyl and propinyl. "Alkylaminocarbonyl" refers to an alkylaminocarbonyl group, wherein the alkylamino is as defined above. "Cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro-cyclic carbocycle, preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. The above analysis of the alkyl and cycloalkyl substituents is also applied to the alkyl portions of other substituents, such as, without limitation, alkoxy substituents, alkylamines, alkylketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester and the like. "Cycloalkylalkyl" means a cycloalkyl-alkyl group, wherein the cycloalkyl and alkyl moieties are as described above. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. "Heterocycloalkyl" refers to a ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms. Each ring preferably has 3 to 4 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include purolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphino, 1,3-diazapan, 1,4-diazapan, 1,4-oxazepan and 1,4-oxathiapan. "Heterocycloalkenyl" refers to a heterocycloalkyl as described above, but with at least one double bond. "Heterocycloalkylalkyl" refers to a heterocycloalkylalkyl group, wherein the heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl) methyl, (2-tetrahydrothiofuranyl) methyl. "Heteroalkyl" refers to a straight-chain or branched-chain alkyl group preferably having 2 to 14 carbons, more preferably 2 to 10 atoms in the chain, one or more of which are a heteroatom selected from S, O and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides and the like. "Aryl" as a group or part of a group implies (i) an optionally substituted aromatic, monocyclic or polycyclic carbocyclic carbocycle (ring structure with ring atoms which are all carbons) which preferably has from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl and the like; (ii) x optionally substituted, partially saturated bicyclic aromatic carbocyclic moiety, wherein a phenyl group and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The aryl group may be substituted by one or more groups. "Arylalkenyl" means an aryl-alkenyl- group, wherein the aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylallyl. "Arylalkyl" means an aryl-alkyl group, wherein the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain an alkyl Cl-5 moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenylmethyl. "Cycloalkenyl" means a system of monocyclic or non-aromatic, optionally substituted, monocyclic rings containing at least one carbon-carbon double bond and preferably having from 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted with one or more substituent groups. "Heteroaryl" refers to a fused, aromatic monocyclic or polycyclic heterocycle (ring structure preferably having a 5- to 7-membered aromatic ring with one or more heteroatoms selected from N, O, and S). Typical heteroaryl substituents include furyl, thienyl, pinol, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, indole, benzimidazole and the like. "Heteroarylalkyl" means a heteroaryl-alkyl group, wherein the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain xm lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. "Lower alkyl" as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be linear or branched, having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons, such as methyl , ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary butyl). In formula I, as well as in formulas la-Ib which define subgroups of compounds within formula I, a benzimidazole ring system is shown. Within this system of rings, there are substitutable positions in the positions of the ring 4, 5, 6 and 7. In each of the formulas I, the and Ib, there is a requirement to join an acidic residue in one of the positions of ring. This acidic moiety may be provided, but without limitation, by groups containing a hydroxamic acid or derivatives of salts of said acid which, when hydrolyzed, would provide the acidic moiety. In certain embodiments, the acidic moiety may be attached to the position of the ring through an alkylene group, such as -CH2- or -CH2CH2-, or an alkenyl group such as -CH = CH- The preferred positions for the union of the acidic moiety are the ring positions 5 and 6. It is understood that the isomeric forms including diastereoisomers, enantiomers, tautomers and geometric isomers in the isomer of "E" configuration are included in the family of compounds of formula I "or" Z "or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers and geometric isomers can be separated by physical and / or chemical methods and by those skilled in the art. Some of the compounds of the embodiments described can exist as individual stereoisomers, racemates and / or mixtures of enantiomers and / or diastereomers. All these individual stereoisomers, racemates and mixtures thereof are intended to be within the scope of the object described and claimed. In addition, formula I aims to cover, when appropriate, the solvated and unsolvated forms of the compounds. Accordingly, each formula includes compounds with the indicated structure, for example the hydrated and non-hydrated forms. In addition to the compounds of the formula, the HDAC inhibiting agents of the various embodiments include pharmaceutically acceptable salts, prodrugs and active metabolites of said compounds and the pharmaceutically acceptable salts of said metabolites. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compounds identified above, and include the acid addition salts and pharmaceutically acceptable base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula I can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include hydrochloric, sulfuric and phosphoric acid. Suitable organic acids can be selected from the classes of organic acids aliphatic, cycloaliphatic, aromatic, heterocyclic and sulfonic carboxylic acids, of which formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric acids are examples. , fumaric, maleic, alkylsulfonic, arylsulfonic. The base addition salts of the compounds of the formula I include the metal salts prepared from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts prepared from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA 1990. In the case of agents that are solid, those skilled in the art understand that the compounds of the invention, agents and salts can exist in different crystalline or polymorphic forms, all of which are intended to be within the present invention and specific formulas. "Prodrug" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis, reduction or oxidation) to a compound of formula I. For example, a prodrug ester of xm compound of formula I containing a group hydroxyl may be convertible by hydrolysis in vivo in the progenitor molecule. Suitable esters of the compounds of the formula (I) containing a hydroxyl group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthates, gestisinates, isothionates, di-p-toluyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. As another example, an ester prodrug of a compound of formula I containing a carboxy group can be converted by hydrolysis in vivo into the progenitor molecule. (Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18: 379, 1987). Possible HDAC inhibitors are, for example, those having an IC 50 value of 1 μM or less. The administration of the compounds within formula I to humans can be by any of the accepted modes for enteral administration, such as orally or rectally, or by parenteral administration such as the subcutaneous, intramuscular, intravenous and intradermal routes. The injection can be in bolus or by constant or intermittent infusion. In general, the active compound is included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, for example, cancerous rumors, than to normal cells. The term "therapeutically effective amount" or "therapeutic amount" is an amount sufficient to produce beneficial or sought-after results. An effective amount can be administered in one or more administrations. In general, an effective amount is sufficient to alleviate, alleviate, stabilize, reverse, slow or delay the progression of the pathological state. To use the compounds of the invention, they can be administered in any form or manner that makes the compound bioavailable. One skilled in the art of preparing formulations can easily select the suitable form and administration mode, according to the particular characteristics of the selected compound, the condition to be treated, the condition of the treated condition and other relevant circumstances. Refer to Remingtons Pharmaceutical Sciences, 18th edition, Mach Publishing Co. (1990) for additional information. The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, although effective in themselves, are generally formulated and administered in the form of their pharmaceutically acceptable salts, since in general these salts are more stable, crystallize more easily and have greater solubility. However, in general the compounds are used in the form of pharmaceutical compositions which are formulated according to the mode of administration of interest. As such, in another embodiment, the present invention provides a pharmaceutical composition that includes a compound of the formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in the ways well known in the art. The compounds of the invention may be used or administered in combination with one or more additional drug (s) which are chemotherapeutic drugs or drugs and / or HDAC inhibitor methods (e.g., surgery, radiotherapy) for the treatment of the disorder. / mentioned illness. The components can be administered in the same formulation or in different formulations. If administered in different formulations, the compounds of the invention can be administered sequentially or simultaneously with the other drug (s). The pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, in addition to sterile powders for reconstitution into sterile injectable solutions or dispersions just before use. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and the corresponding suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper flowability can be maintained, for example, by the use of cover materials such as lecithin, by maintenance of the required particle size, in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example paraben, chlorobutanol, phenol sorbic acid and the like. It may also be convenient to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be prepared by including agents that delay absorption, such as aluminum monostearate and gelatin. If desired, and for a more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes and microspheres. Injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by the incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium. Before its use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and / or) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and acid. silicic, b) fixatives such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pylolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution delay agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate , h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycols olides, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft or hard gelatin capsules by excipients such as lactose or milk sugar, in addition to high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents, and may also have a composition by which they only release the active ingredient (s), or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes. If desired and for a more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems, such as polymer matrices, liposomes and microspheres.

The active compounds may also be in microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active components, the suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and the corresponding mixtures. Preferably, compositions for rectal or vaginal administration are suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax that are solid at temperature environment and fluids at body temperature, so they melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of the present invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required. A preferred dosage would be in the range of approximately 0.01 to 300 mg per kilogram of coforal weight per day. A more preferred dosage would be in the range of 0.1 to 100 mg per kilogram of coforal weight per day, more preferably from 0.2 to 80 mg per kilogram of coforal weight per day, with even greater preference from 0.2 to 50 mg per kilogram of coforal weight per day. An adequate dose can be administered in multiple sub-doses per day. As discussed above, the compounds of the described embodiments inhibit histone deacetylases. The enzymatic activity of a histone deacetylase can be measured by known methodologies [Yoshida M. et al, J. Biol. Chem., 265, 17174 (1990), J. Taunton et al, Science 1996 272: 408]. In certain embodiments, the histone deacetylase inhibitor interacts and reduces the activity of more than one known histone deacetylase in the cell. In some other embodiments, the histone deacetylase inhibitor interacts and predominantly reduces the activity of a histone deacetylase, for example HDAC-1, HDAC-3 or HDAC-8, which belong to the HDAC class I enzymes [De Ruijter AJM et al. al, Biochem, J., 370. 737-749 (2003)]. Certain preferred inhibitors of histone deacetylase are those that interact and reduce the activity of a histone deacetylase that is involved in tumorigenesis, and these compounds may be useful for the treatment of proliferative diseases. Examples of such diseases or pathological conditions of cell proliferation include cancer and / or any metastases, psoriasis and restenosis. The compounds of the invention may be of particular importance for the treatment of tumors such as breast cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal, gastric and cerebral cancer. In addition, the compounds of the invention may be useful for the treatment of a proliferative disease that is refractory to treatment with other chemotherapeutic agents.; and for the treatment of hyper-proliferative pathological conditions such as leukaemias, psoriasis, restenosis. Additional compounds of the various embodiments described herein may be useful for the treatment of neurodegenerative diseases and inflammatory diseases and / or diseases of the immune system. Preferably, the disorder is selected from the group consisting of cancer, inflammatory diseases and / or immune system disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, chronic neurodegenerative diseases and acute such as Huntington's disease, Parkinson's disease, nervous tissue disorders and infectious diseases such as fungal, bacterial and viral infections. In another embodiment, the disorder is a proliferative disorder. The histone deacetylase inhibitors of the invention have significant antiproliferative effects and favor differentiation, cell cycle arrest in Gl or G2 phases and apoptosis.

Synthesis of deacetylase inhibitors The agents of the various embodiments can be prepared by the reaction routes and synthesis schemes described below, which use the techniques available in the art by means of readily available initial materials. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described can easily be adapted to prepare numerous other agents of the different embodiments. For example, the synthesis of non-exemplified compounds can be achieved successfully by modifications apparent to those skilled in the art, for example, through adequately protective interference groups, by being modified to other suitable reagents known in the art, or by routine modifications of the reaction conditions. A list of suitable protecting groups is found in organic synthesis in T. W. Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. As an alternative, other reactions described herein or known in the art will be recognized for their applicability for the preparation of other compounds of the various embodiments. 5 Useful reagents for the synthesis of compounds can be obtained or prepared according to techniques known in the art. Unless otherwise indicated, in the examples described below the temperatures of the following descriptions are in degrees Celsius and all parts and percentages are by weight, unless otherwise stated. Various starting materials and other reagents were purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide 5 (DMF) were purchased from Aldrich in SureSeal flasks and used as received. All solvents were purified by standard methods in the art unless otherwise indicated. The reactions set forth below were performed under positive pressure of nitrogen, argon or with a drying tube, at room temperature or ambient (unless otherwise stated), in anhydrous solvents, and the reaction reaction vessels are fitted with partitions. of rubber to introduce substrates and reagents by means of a syringe. The glass material was dried in the oven and / or heat. Analytical thin-layer chromatography of silica gel on glass base was carried out in 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v / v). The reactions will be tested by TLC and terminated according to criteria by the consumption of the starting material. TLC plates were visualized by UV absorption or by p-anisaldehyde aerosol reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20% by weight ethanol) activated by heat, or by iodide chamber staining. In general, work was carried out by duplication of the reaction volume with the reaction solvent or the extraction solvents, and then washed with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated) . The solutions of the products were dried over anhydrous sodium sulfate before filtration and the evaporation of the solvents under reduced pressure in a rotary evaporator, and the solvents were removed as solvents. Flash column chromatography was performed [Still et al, J. Org. Chem., 43, 2923 (1978)] with Merck grade E silica gel (47-61 mm) and a silica gel: crude material ratio of approximately 20: 1 to 50: 1, unless otherwise specified another thing. Hydrogenolysis was carried out at the indicated pressure or at ambient pressure. 1 H NMR spectra were recorded by a Bruker instrument operating at 400 MHz and the 13 C-NMR spectra were recorded operating at 100 MHz. The NMR spectra are obtained as CDCB solutions (reported in ppm), with chloroform as reference standard (7.25 ppm and 77.00 ppm) or CD30D (3.4 and 4.8 ppm and 49.3 ppm), or an internal standard of tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents are used as needed. When multiplicities of peaks are reported, the following abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = extended, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hertz. Mass spectra were obtained by LC / MS, either in ESI or in APCI. All melting points are given without connections. All final products were more than 90% pure (by HPLC with wavelengths of 220 nm and 254 nm). The following examples are intended to illustrate the embodiments described and not to be understood as limitations. Additional compounds other than those described below can be prepared by the reaction scheme or appropriate variations or the corresponding modifications.

Synthesis Scheme I illustrates the process used to prepare compounds of the formula Ib, wherein X and Y are hydrogens, the compounds (VI) of the formula can be prepared by means of an analogous procedure, for example, by selecting the appropriate departure. For example, in the case where Z is -CH = CH- and is attached to the C5 position in the formula Ib, such compounds can be synthesized by means of an analogous method illustrated in scheme I, starting with xm substituted cinnamic acid ( for example, trans-3-nitro-4-chloro cinnamic acid), appropriate amine component (R1NH2), aldehyde or carboxylic acid component (R2CHO or R2COOH) and appropriate hydroxylamine or N-alkylhydroxylamine (NHR30H, where R3 is as it was previously defined in the formula la).

Scheme I Specifically, the hydroxamate compounds of the formula Ib can be synthesized through the synthetic route indicated in Scheme I. The reaction of trans-4-chloro-3-nitrocinnamic acid (I) with an amine in the presence of a base (e.g., triethylamine) in a suitable solvent (e.g., dioxane) gave (II). Treatment of (II) in methanol under acid catalysis (e.g., sulfuric acid) resulted in the esterification that it supplied (III). The nitro group of (III) can be reduced by means of an appropriate reducing agent (for example, tin chloride) and the resulting phenylenediamine cyclized with an aldehyde to give (V). The hydroxamate compounds (VI) were obtained by means of a known synthesis method (J. Med. Chem., 2002, 45, 753-757). An alternative method to prepare (VI) is by coupling (IV) with an appropriate acid and then cyclizing by heating with acetic acid (J. Med. Chem. 2001, 44, 1516-1529).

Scheme II Scheme II illustrates another alternative procedure used to prepare compounds of formula Ib, where X and Y are hydrogens, R2 = Cy-Ll-W-L2. For example, in the case where Z is -CH = CH- and is attached to the C5 position in the formula Ib, such compounds (XV) can be synthesized by means of an analogous method illustrated in Scheme II starting with (III) appropriate, appropriate Fmoc-protected amino acids, appropriate acid chlorides or aldehydes and hydroxylamine. More specifically, for example, the hydroxamate compounds of the formula Ib, where X and Y are hydrogens, R2 = Cy-Ll-W-L2 and Z are bonded to the C5 position, can be synthesized via the indicated synthesis route in Scheme II. Suitable intermediates (III) were reduced with tin chloride in the corresponding diamines (VII). The coupling reaction with appropriate Fmoc-protected amino acids in the presence of PyBOP resulted in two coupling products (VIII) and (IX). Without further separation, it was subjected to (VIII) and (LX) to cyclization under acidic conditions and (X) was obtained. The key intermediate (XI) can be obtained by treatment of (X) with 20% piperidine. Treatment of (XI) with an appropriate acid chloride or appropriate xm sulfonyl chloride resulted (XII) and the subject compounds (XIII) were obtained using a similar method described above. When (XI) was reacted with an appropriate aldehyde under reduced conditions (NaBH (OAc) 3 / CH3COOH), (XIV) was obtained and can be transformed into the corresponding hydroxamate derivatives (XV) by means of the same methods described with anteriority.

Scheme III The hydroxamate compounds of the formula I can also be prepared through a solid phase synthesis. Scheme III illustrates the synthesis of the hydroxamate compounds of formula Ib. For example, in the case where Z is -CH = CH- and is attached to the C5 position, in the formula Ib, such compounds (VI) can be synthesized by means of an analogous method illustrated in Scheme III starting from SASRIN resin. , an appropriate hydroxylamine (eg, 0- (2,4-dimethoxy-phenyl) -hydroxylamine), an appropriate cinnamic acid (e.g., trans-4-chloro-3-nitro-cinnamic acid), an appropriate amine and an aldehyde. Specifically, for example, the hydroxamate compounds (VI) of the formula Ib can be synthesized via the synthetic route indicated in Scheme IV. The SASRTN resin treated with 0- (2,4-dimethoxy-phenyl) -hydroxylamine under reductive conditions (NaBH3CN / CH3COOH) in an appropriate solvent gave the corresponding compound (XVI). Reacted (XVI) with trans-4-chloro-3-nitro-cinnamic acid in the presence of 4-dimethylaminopyridine to obtain (XVII). Subsequent treatment of (XVII) with appropriate amines resulted (XVIII). It was treated (XIX) by cleavage of the corresponding resin (XVIII). Without further purification, (XIX) was transformed into the corresponding hydroxamate (VI) compounds using the method described above.

Scheme IV Scheme IV illustrates another procedure for preparing the hydroxamate compounds of the formula I. For example, in the case where Z is -CH2CH2- and is attached to the C5 position in the formula Ib, such compounds can be synthesized by means of a analogous method illustrated in Scheme IV starting with the appropriate intermediates (V) through reduction and then the resulting product (XX) can be transformed into the corresponding hydroxamate compounds (XXI) of the formula Ib. The compounds (XXIII), in which Z is a cyclopropylene group (X ^ X) and is attached to the C5 position in the formula Ib, can be prepared from V by treatment with (CH3) 3S (0) i5 and the resulting cyclopropyl derivatives (XXII) were converted to the hydroxamate derivative derivatives (XXIII) according to the methods described above for the preparation of hydroxamic acid.

Scheme V Scheme V illustrates another synthesis method of the hydroxamate compounds of the formula I. For example, in the case where Z is -CH = CH- and is attached to the C5 position in the formula Ib, such compounds can be synthesized by means of an analogous method illustrated in Scheme V starting with the appropriate intermediates (II) through reduction and then the resulting product (XXIV) was cyclized, without further purification, to give (XXV). The (XXV) was treated with an appropriate alkyl halogenide (e.g., benzyl bromide) in the presence of an inorganic base (e.g., sodium carbonate) in an appropriate solvent to give (XXVI). Treatment of (XXVI) with hydrogen peroxide in acetic acid led to (XXVIII). Using the same method as previously described, both (XXVI) and (XXVIII) were transformed into the corresponding hydroxamate compounds (XXVII) and (XXIX), respectively. The following preparation and the following examples are provided to allow art specialists a clearer understanding and to put into practice the object of the present. They should not consider the scope of the description as limiting, but merely illustrative and representative of it.

Example 1 Preparation of N-hydroxy-3-rl-β-hydroxy-propyl) -2-f2-phenyl-propyl-1H-benzimidazol-5-ill-acrylarnide (1 Step 1 To a pre-stirred solution of trans-acid - 3-chloro-3-nitrocinnamic acid (1.0 g, 4.4 mmol) in dioxane (10 mL) was added triethylamine (2 mL), 3-amino-1-propanol (1.5 mL), and the resulting solution was heated to 85 ° C. After 19 hours, the mixture was cooled to room temperature, the solvent was removed in vacuo, water (100 ml) was added to the residue and the pH was adjusted to 1-1.5, and the precipitate was collected and washed with cold water twice. The product 3- [3-nitro-4- (hydroxypropylamine) -phenyl] -acrylic acid was obtained as a yellow solid substance (1.10 g, 95%) MS (m / z): 267 (MH ) + Step 2 Concentrated sulfuric acid (0.5 ml) was added to the solution of trans-Aμ (3-hydroxypropylamine) -3-nitrocinnamic acid, (1.10 g, 3.9 mmol) and MeOH (15 ml). heated to reflux for 18 hours. The reaction mixture was cooled to -10 ° to -15 ° C for 3 hours. 3- [3-Nitro-4- (hydroxypropylamine) -phenyl] -acrylic acid methyl ester was collected as a yellow crystalline solid substance (1.06 g, 91%). MS (m z): 281 (MH) +. Step 3 To a previously stirred solution of methyl trans- (3-hydroxypropylamine) -3-nitrocinnamate (280 mg, 1.0 mmol) and 3-phenylbutyraldehyde (500 mg, 3.4 mmol) in glacial acetic acid (5 ml), added tin chloride (1.18 g, 10.0 mmol). The resulting solution was heated to 45 ° C for 17 hours and then cooled to room temperature. The solvent was removed in vacuo. Water (20 ml) and dichloromethane (20 ml) were added to the residue and stirred for 30 minutes. The organic layer was dried (MgSO 4), filtered and concentrated to an oily residue. 100 ml of diethyl ether was added and stirred for 4 hours. The product 3- [1- (3-hydroxy-propyl) -2- (2-phenyl-pro? Il) -lH-benzimidazol-5-yl] -acrylic acid methyl ester was obtained in a yield of 34.9% ( 132.0 mg). MS (m / z): 379 (MH) +. Step 4 Sodium methoxide (30% in methanol) was added (782 mg, 4.1 mmol) to a previously stirred solution of 3- [1- (3-hydroxy-propyl) -2- (2-phenyl-propyl) -lH-benzimidazol-5-yl] -acrylic acid methyl ester (130 mg 0.34 mmol and hydroxylamine hydrochloride (242 mg, 3.4 mmol in MeOH (1.5 ml) .The reaction mixture was stirred continuously for 40 minutes at room temperature and then poured into a solution of ice water containing 1.0 ml of water. Concentrated hydrochloric acid The mixture was extracted with dichloromethane The organic layer was dried (MgSO.sub.4), filtered and concentrated The desired product was separated by preparative reverse phase HPLC After freeze drying 7.8 mg (6%) of N-hydroxy-3- [l- (3-hydroxy-o-pyl) -2- (2-phenyl-yl) -lH-benzimidazol-5-yl] -acrylamide in powder form HPLC: 96%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 7.22 min; 92% 1 H NMR (400 MHz, DMSO-d 6) d 1.35 (3 H, d, J = 6.5 Hz), 1.83 (2 H, m), 3.00-4.00 (6 H, m), 4.33 (2 H, t, J = 7.1 Hz) , 6.55 (1H, d, J = 15.8 Hz), 7.19-7.33 (5H, m), 7.62 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 8.60 Hz), 7.82 (1H, d, J = 8.60 Hz), 7.92 (1H, s), 10.15 (1H, bs), 10.33 (1H, bs). MS (m / z): 380 [MH] +.

Example 2 Preparation of N-hydroxy-3-r 1 - (3 A 5 -trimethoxybenzyl-2-phenyl-2-phenyl-ethyl) -1 H-benzimidazol-5-yl-acrylamide (2) The title compound (2) prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 91%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 7.22 min. 1 H NMR (400 MHz, DMSO-d 6) 53.08 (2H, t, J = 7.72 Hz), 3.48 (2H, t, 7.72 Hz), 3.63 (3H, s), 3.67 (6H, s), 5.58 (2H, s), 6.59 (2H, s), 7.22-7.31 (7H, m), 7.63 (1H, d, J = 15.78 Hz), 7.71 (1H, d, J = 8.76 Hz), 7.83 (1H, d, J = 8.76 Hz), 7.98 (1H, s), 11.00 (2H, bs). MS (m / z): 488 [MH] +.

Example 3 Preparation of N-hydroxy-3-r2-4-benzyloxy-3-methoxy-phenyl) -l-methyl-1H-benzimidazole-5-in-acrylamide () The title compound (3) was prepared in accordance with the procedures described in Example 1, using the appropriate starting materials. HPLC: 92%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 7.32 min. 1 H NMR (400 MHz, DMSO-d 6) d 3.87 (3H, s), 4.01 (3H, s), 5.24 (2H, s), 6.56 (1H, d, J = 15.80 Hz), 7.32-7.50 (8H, m), 7.74 (1H, d, J = 8.72 Hz), 7.88 (1H, d, J = 8.72 Hz), 7.94 (1H, s), 10.85 (1H, bs). MS (m / z): 431 [MH] +.

Example 4 Preparation of N-hydroxy-3-r 2 -f 4 -benzyloxy-3-methoxy-phenyl-V 3 -hydroxy-propyl V-1 H-benzimidazol-5-yl-acrylamide (4) The title compound (4) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 95%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 6.82 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.96 (2H, m), 3.88 (3H, s), 4.48 (2H, t, J = 7.12 Hz), 5.24 (2H, s), 6.56 (1H, d, J = 15.76 Hz), 7.32-7.50 (8H, m), 7.65 (1H, d, J - 15.76 Hz), 7.74 (1H, d, J = 8.60 Hz), 7.91 (1H, d, J = 8.60 Hz) , 7.95 (1H, s), 10.85 (1H, bs). MS (m / z): 474 [MH] +.

Example 5 Preparation of N-hydroxy-3-r 1 - (2-hydroxy-ethyl-V 2 - (- methoxy-phenyl-VlH-benzimidazol-5-yl] -acrylamide] 5 The title compound (5) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 98%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% of B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 4.12 min 1 H NMR (400 MHz, DMSO-d6) d 3.80 (2H, t, J = 5.36 Hz ), 3.87 (3H, s), 4.39 (2H, t, J = 5.36 Hz), 6.56 (1H, d, 15.72 Hz), 7.17 (2H, d, J = 8.88 Hz), 7.61 (1H, d, J = 8.52 Hz), 7.62 (1H, d, J = 15.72 Hz), 7.78 (1H, d, J = 8.52 Hz), 7.88 (1H, d, J = 8.88 Hz), 7.90 (1H, s), 10.77 ( 1H, bs). MS (m / z): 354 [MH] +.

Example 6 Preparation of N-hydroxy-3-f 1-f 2,3-hydroxy-propyl -2- (4-methoxy-phenyl ') -1H-benzimidazol-5-ü] -acrylamide (6 The title compound (6 ) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 98%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5 -65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 3.39 min NMR (400 MHz, DMSO-d6) d 3.90 ( 3H, s), 4.01 (1H, m), 4.35 (2H, m), 4.58 (2H, dd, J = 2.48 and 14.48 Hz), 6.62 (1H, d, J = 15.84 Hz), 7.27 (2H, d , J = 8.92 Hz), 7.68 (1H, d, J = 15.84 Hz), 8.01 (4H, m), 10.13 (1H, bs), MS (m / z): 383 [M] +.

Example 7 Preparation of N-hydroxy-3-r2- (4-benzyloxy-3-methoxy-phenpVl-f2.3-hydroxy-propyl-1H-benzimidazol-5-ill-acrylamide (7) The title compound (7) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 100%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.06 min. NMR (400 MHz, DMSO-d6) d 4.04-4.38 (3H, m), 4.05 (3H, s), 4.49 (2H, m), 5.22 (2H, s), 6.55 (1H, d, J = 15.72 Hz ), 7.29-7.94 (11H, m), 8.01 (1H, s). MS (m / z): 490 [MHJ +.

Example 8 Preparation of N-hydroxy-3-r l- (.3-hydroxy-propyl) -2-f 2-pyridyl VI H-benzimidazol-5-ill-acrylamide (9) The title compound (9) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 93.7%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid; B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.61 min. NMR (400 MHz, DMSO-d6) d 3.20-3.37 (4H, m), 3.90 (1H, m), 4.90 ^ 1.95 (2H, m), 6.54 (1H, d, J = 15.52 Hz), 7.98 (1H , s), 8.04 (1H, m), 8.27 (1H, m), 9.73 (1H, d, J = 8.0 Hz). MS (m / z): 355 [MH] +.

Example 9 Preparation of N-hydroxy-3-ri- (2-Mdroxy-ethyl-V2-f4-pyridyl) -lH-benzimidazol-5-ill-acrylamide (10) The title compound (10) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.14 min. NMR (400 MHz, DMSO-d6) d 3.78 (2H, t, J = 5.80 Hz), 4.43 (2H, t, J = 5.80 Hz), 6.50 (1H, d, J = 15.80 Hz), 7.82 (2H, d, J = 8.56 Hz), 7.94 (1H, s), 8.00 (2H, d, J = 5.97Hz), 8.81 (2H, d, J = 5.97 Hz). MS (m / z): 325 [MH] +.

Example 10 Preparation of N-hydroxy-3- [l-0-hydroxy-propyl -2- (4-pyridif) -lH-benzimidazol-5-ill-acrylamide (11 The title compound (11) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 98.2%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% of B during 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.61 min NMR (400 MHz, DMSO-d6) d 1.91 (2H, m), 3.37 (2H, t, J = 5.84 Hz), 4.49 (2H, t, J = 7.84 Hz), 6.54 (1H, d, J = 15.52 Hz), 7.98 (1H, s), 8.06 (2H, d, J = 6.26 Hz), 8.90 (2H, d, J = 626 Hz) MS (m / z): 339 [MH] +.

Example 11 Preparation of N-hydroxy-3-r 1-f 3-pyridylmethyl V 2 -i 2 -phenyl-etif) -l H-benzimidazol-5-ill-acrylamide (12 The title compound (12) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 97.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% of B during 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 3.32 min NMR (400 MHz, DMSO-d6) d 3.11 (2H, t, J = 8.40 Hz), 5.71 (2H, s), 6.51 (1H, d, J = 15.80Hz), 7.20-7.31 (6H, m), 7.43 (1H, m), 7.40-7.57 (4H, m), 7.94 ( 1H, s), 8.57 (1H, s) MS (m / z): 399 [MH] +.

Example 12 Preparation of N-hydroxy-3-ri-f3-hydroxy-propyl -2-f2-pyridyl-lH-benzimidazol-5-ill-acrylamide f 13) The title compound (13) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 98.3%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.37 min. NMR (400 MHz, DMSO-d6) d 1.98 (2H, m), 3.30 (2H, m), 4.86 (2H, t, J = 7.00 Hz), 6.51 (1H, d, J = 15.76 Hz), 7.77 ( 2H, d, J = 8.56 Hz), 7.94 (1H, s), 8.05 (1H, m), 8.30 (1H, d, J = 7.92 Hz), 8.78 (1H, d, J = 4.28 Hz). MS (m / z): 339 [MH] +.

Example 13 Preparation of N-hydroxy-3- [l-f3-hydroxy-propyl-2-phenethyl-lH-benzimidazol-5-yl-acrylamide f 14) The title compound (14) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 97.3%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.63 min. NMR (400 MHz, DMSO-d6) d 1.87 (2H, m), 3.18 (2, t, J = 7.40 Hz), 4.41 (2H, t, J = 7.0 Hz), 6.57 (1H, d, J = 17.60 Hz), 7.15 (5H, m), 7.64 (1, d, J = 17.60 Hz), 7.89 (1H, d, J = 8.64 Hz), 7.95 (1H, s). MS (m / z): 366 [MH] +.

Example 14 Preparation of N-hydroxy-3-f2-phenethyl-1- (pyridin-2-yl) methyl-1H-benzimidazol-5-yl) -acrylamide (16) The title compound (16) was prepared in accordance with the procedures described in Example 1, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.11 min. NMR (400 MHz, DMSO-d6) d 3.31 (2H, t, J = 7.56 Hz), 5.81 (2H, s), 6.57 (1H, d, J = 17.60 Hz), 7.20-7.36 (6H, m), 7.52 (1H, m), 7.64 (1H, d, J = 17.60 Hz), 7.68 (1H, d, J = 8.48 Hz), 7.77 (1H, d, J = 8.48 Hz), 7.87 (1H, m), 8.44 (1H, d, J = 3.92Hz). MS (m / z): 399 [MH] +.

Example 15 Preparation of N-hydroxy-3-r l- (3-dimethylamino-2. -dimethyl-propy) -2-phenetif-1 H-benzimidazol-5-yl-acrylamide (17) The title compound (17 ) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna Cl 8 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.13 min. NMR (400 MHz, DMSO-d6) d 1.08 (6H, s), 2.89 (6H, s), 4.30 (2H, s), 6.54 (1H, d, J = 15.80 Hz), 7.03 (1H, s), 7.16 (1H, s), 7.22-7.32 (6H, m), 7.65 (1H, d, J = 15.80 Hz), 7.91 (1H, s). MS (m / z): 421 [MH] +.

Example 16 Preparation of N-hydroxy-3- [2-benzyloxymethyl-1- (3-hydroxy-propyl-1H-benzimidazol-5-ill-acrylamide (19)) The title compound (19) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 98.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% of B for 15.5 min , solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 4.50 min 1 H NMR (400 MHz, DMSO-d6) d 1.94 (2H, m), 3.43 ( 2H, t, J = 5.8 Hz), 4.42 (2H, t, J = 7.2 Hz), 4.67 (2H, s), 4.97 (2H, s), 6.53 (1H, d, J = 15.8 Hz), 7.38 ( 5H, m), 7.63 (1H, d, J = 15.8 Hz), 7.67 (1H, d, J = 9.1 Hz), 7.80 (1H, d, J = 8.6 Hz), 7.90 (1H, s), 10.77 ( 1H, bs). MS (m / z): 382 [MH] +.

Example 17 Preparation of N-hydroxy-3-ri- (3-hydroxy-propyl) -2-thiophen-3-yl-lH-benzimidazol-5-yl] -acrylamide (20) The title compound (20) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 97.9%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid; ÜV 254): 3.06 min. 1 H NMR (400 MHz, DMSO-d 6), d 1.98 (2 H, m), 3.49 (2 H, t, J = 5.8 Hz), 4.56 (2 H, t, J = 7.2 Hz), 6.56 (1 H, d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.69 (1H, d, J = 8.7 Hz), 7.75 (1H, dd, J = 5.1 Hz, 1.2 Hz), 7.89 (2H, m) , 7.93 (1H, s), 8.42 (1H, dd, J = 2.6 Hz), 10.90 (1H, bs); MS (m / z): 344 [MH] +.

Example 18 Preparation of N-hydroxy-3-ri- (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazol-5-yl-acrylamide (21) The title compound (21) was prepared according to procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.14 min. 1 H NMR (400 MHz, DMSO-d 6), d 1.01 (6H, d, J = 6.6 Hz), 1.94 (2H, m), 2.28 (1H, m), 3.04 (2H, d, J = 7.4 Hz), 3.47 (2H, t, J = 5.8 Hz), 4.46 (2H, t, J = 7.1 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.73 ( 1H, d, J = 8.6 Hz), 7.89 (1H, d, J = 8.6 Hz), 7.94 (1H, s). MS (m / z): 318 [MH] +.

Example 19 Preparation of N-hydroxy-3- l- (3-hydroxy-propyl) -2-octyl-lH-benzimidazole-5-in-acrylamide (23) The title compound (23) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 7.38 min. 1 H NMR (400 MHz, DMSO-d 6) d 0.86 (3 H, t, J = 6.8 Hz), 1.32 (10 H, m), 1.83 (2 H, m), 1.94 (2 H, m), 3.12 (2 H, t, J = 7.7 Hz), 3.46 (2H, t, J = 5.8 Hz), 4.44 (2H, t, J = 7.0 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.64 (1H, d, J = 15.8 Hz), 7.71 (1H, d, J = 8.6 Hz), 7.87 (1H, d, J = 8.6 Hz), 7.92 (1H, s). MS (m / z): 374 [MH] +.

Example 20 Preparation of N-hydroxy-r2-cyclohexyl-1- (3-hydroxy-propyl) -lH-benzimidazol-5-ill-acrylamide (24) The title compound (24) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 98.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H 0 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 7.38 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.28-2.03 (12H, m), 3.33 (1H, m), 3.47 (2H, t, J = 5.7 Hz), 4.51 (2H, t, J = 6.9 Hz) , 6.58 (1H, d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.76 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 8.7 Hz), 7.93 (1H, s), 10.85 (1H, bs). MS (m / z): 344 [MH] +.

Example 21 Preparation of N-hydroxy-3- (2-isobutyl-1-phenethyl-1H-benzimidazole-5-ill acrylamide (25) The title compound (25) was prepared according to the procedures described in Example 1 , using the appropriate starting materials HPLC: 99.1%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 6.51 min 1 H NMR (400 MHz, DMSO-d6) d? .90 (6H, d, J = 6.6 Hz), 2.10 (1H, m), 2.70 (2H, d, J = 7.3 Hz), 3.11 (2H, t, J = 7.0 Hz), 4.66 (2H, t, J = 7.0 Hz), 6.57 (1H, d, J = 15.8 Hz), 7.14 (2H, m), 7.26 (3H, m), 7.64 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.86 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 13C NMR (100 MHz, DMSO-d6) d 22.0.26.9, 33.3, 34.5, 45.8, 113.0, 114.3, 119.7, 123.7, 126.9, 128.5, 129.0, 132.2, 132.7 , 137.2, 137.8, 154.4, 162.5, MS (m / z): 364 [MH] +.

Example 22 Preparation of N-hydroxy-3- (L2-diphenethyl-lH-benzimidazol-5-yl] -acrylamide (26) The title compound (26) was prepared according to the procedures described in Example 1, using the Appropriate starting materials HPLC: 98.3%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% of trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 7.68 min. 1 H NMR (400 MHz, DMSO-d6) d 2.99 (4H, m), 3.09 (2H, m), 4.59 (2H , t, J = 6.9 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.07 (2H, m), 7.23 (6H, m), 7.31 (2H, m), 7.64 (1H, d, J = 15.5 Hz), 7.66 (1H, d, J = 7.2 Hz), 7.78 (1H, d, J - 8.6 Hz), 7.92 (1H, s), 13C NMR (100 MHz, DMSO-d6) d 27.0, 31.9, 34.5, 45.6, 112.7, 114.7, 119.4, 123.5, 126.5, 126.9, 128.3, 128.5, 129.0, 131.8, 133.0, 137.3, 138.0, 139.5, 154.6, 162.6, MS (m / z): 412 [MH] +.

Example 23 Preparation of N-hydroxy-3- (2-phenethyl-1- (2-pyridin-3-yl-ethyl) -lH-benzimidazole-5-in-acrylamide (27) The title compound (27) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 99.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 3.42 min 1 H NMR (400 MHz, DMSO-d6) d 3.10 (4H, m), 3.28 (2H, t), 4.63 (2H, t) 6.53 (1H, d), 7.22-7.33 (7H, m), 7.54-7.74 (4H, m), 8..5 (2H, d) 10.88 (1H, bs) .MS (mz): 413 [MH] +.

Example 24 Preparation of N-hydroxyl? -Fl- (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazole-5-iH-propionamide (29) The title compound (29) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 99.6%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.88 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.00 (6H, d, J = 6.4 Hz), 2.06 (2H, m), 2.27 (1H, m), 2.42 (2H, t, J = 7.6 Hz), 3.05 -3.11 (4H, m), 3.57 (2H, t, J = 6.0 Hz), 4.52 (2H, t, J = 7.2 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.56 (1H, s) , 7.78 (1H, d, J = 8.0 Hz); 13C NMR (100 MHz, MeOD) d 20.6 (2C), 27.2, 30.4, 30.6, 32.7, 33.5, 41.5, 57.0. 112.0. 112.3, 112.4, 126.3, 129.9, 139.6, 152.3, 169.4. MS (m / z): 320 [MH] +.

EXAMPLE 25 Preparation of N-hydroxy-3-Uf 3- (2-oxo-pipolidin-1-yl-Vpropi-1-2-phenethyl-1H-benzimidazol-5-yl} -acrylamide (30) The title compound (30) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.88 min 1 H NMR (400 MHz, DMSO-d6) d 1.84 (4H, m), 3.14-3.41 (8H, m), 4.29 (2H, t, J = 7.04 Hz), 6.54 (1H, d, J = 15.76 Hz), 7.21-7.33 (5H, m), 7.62 (1H, d, J = 15.76 Hz), 7.71 (1H, d, J = 8.36 Hz), 7.84 (III, d, J = 8.36 Hz), 7.93 (1H, s) MS (m / z): 433 [MH] +.

Example 26 Preparation of N-hydroxy-3-r 1 - (3-morpholin-4-propyl-1-phenethyl-1 H-benzimidazol-5-yl-acrylamide (31) The title compound (31) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.16 min 1 H NMR (400 MHz, DMSO-d6) d 2.12 (2H, m), 3.11 (6H, m), 3.39 (2H, t, J = 7.44 Hz), 4.39 (2H, t, J = 7.01 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.23-7.33 ( 5H, m), 7.62 (1H, d, J = 15.8 Hz), 7.71 (1H, d, J = 8.60 Hz), 7.85 (1H, d, J - 8.60 Hz), 7.95 (1H, s). mz): 435 [MH] +.

Example 27 Preparation of 3-r5- (2-hydrocarbamoyl-vinyl) -2-phenethyl-benzyl? I-dazol-1-yl] -propionic acid (32) The title compound (32) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 95.6%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.55 min. 1 H NMR (400 MHz, DMSO-d 6) d 2.74 (2 H, t, J = 6.68 Hz), 4.49 (2 H, t, J = 6.68 Hz), 3.16 (2 H, t, J = 7.44 Hz), 6.52 (1 H , d, J = 15.76 Hz), 7.22-7.33 (5H, m), 7.62 (1H, d, J = 15.76 Hz), 7.66 (1H, d, J = 8.56 Hz), 7.82 (1H, d, J = 8.56 Hz), 7.89 (1H, s), 11.00 (1H, s) MS (m / z): 380 [MH] +.

Example 28 Preparation of N-hydroxy-3- (1-benzyl-2-phenethyl-1H-benzimidazol-5-yl-acrylamide (33) The title compound (33) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A : H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 7.82 min 1 H NMR (400 MHz, DMSO-d6) d 3.08 (2H, t, J = 7.4 Hz), 3.34 (2H, t, J = 7.5 Hz), 5.62 (2H, s), 6.50 (1H, d, J = 15.8 Hz), 7.14 (2H, m), 7.30 (8H, m), 7.63 (3H, m ), 7.92 (1H, s), 10.78 (1H, br), 13C NMR (100 MHz, DMSO-d6) d 27.8, 32.2, 46.8, 112.1, 115.9, 118.6, 123.0, 126.4, 126.8, 127.9, 128.3, 128.4 , 128.9, 131.0, 134.4, 135.7, 138.4, 139.9, 155.3, 162.7, MS (m / z): 398 [MH] +.

Example 29 Preparation of N-hydroxy-3- (1-benzyl-2-isobutyl-1 H-benzimidazol-5-yl) -acrylamide (34) The title compound (34) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 89.2%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 6.07 min. 1 H NMR (400 MHz, CDCB) d 0.92 (6H, d, J = 6.6 Hz), 2.13 (1H, m), 3.02 (2H, d, J = 7.4 Hz), 5.72 (2H, s), 6.54 (1H , d, J = 15.8 Hz), 7.21 (2H, m), 7.35 (3H, m), 7.66 (3H, m), 7.96 (1H, s); 13C NMR (100 MHz, CDCB) d 22.0. 27.2, 34.0. 47.2, 112.8, 114.9, 119.4, 123.7, 126.8, 128.0. 128.9, 131.9, 133.6, 135.3, 138.0. 155.0. 162.6. MS (m / z): 350 [MH] +.

Example 30 Preparation of N-Mdroxy-3- (l-benzyl-lH-benzimidazol-5-yl-acrylamide (35) The title compound (35) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna column C18 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.69 min. 1 H NMR (400 MHz, CD30D) d 5.68 (2H, s), 6.54 (1H, d, J = 15.7 Hz), 7.37 (5H, m), 7.66 (1H, d, J = 15.8 Hz), 7.75 (2H , s), 7.94 (1H, s), 9.36 (1H, br); 13 C NMR (100 MHz, CD30D) d 51.7, 114.8, 116.1, 120.6, 126.5, 129.2, 130.2, 130.4, 135.0. 135.3, 140.1, 165.6. MS (m / z): 294 [MH] +.

Example 31 Preparation of N-hydroxy-3- (2-phenethyl-1-propyl-1 H-benzimidazole-5-y-acrylamide (36) The title compound (36) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 93.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 6.05 min 1 H NMR (400 MHz, CD30D) d 0.90 (3H, t, J = 7.4 Hz), 1.70 (2H , m), 3.20 (2H, m), 3.48 (2H, t, J = 7.1 Hz), 4.21 (2H, t, J = 7.4 Hz), 6.54 (1H, d, J = 15.7 Hz), 7.20 (5H , m), 7.65 (1H, d, J - 15.7 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.6 Hz), 7.84 (1H, s); 13C NMR ( 100 MHz, CD30D) d 11.2, 23.6, 28.7, 34.0, 47.7, 114.4, 114.6, 120.5, 126.3, 128.3, 129.5, 130.0, 132.7, 134.0, 135.2, 139.9, 140.1, 155.5, 165.6, MS (m / z) : 350 [MH] +.

Example 32 Preparation of N-hydroxy-3- (1-propyl-1H-benzimidazol-5-yl-acrylamide (37) The title compound (37) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 95.2%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1 % trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 2.92 min 1 H NMR (400 MHz, CD30D) d 0.97 (3H, t, J = 7.4 Hz), 1.98 (2H, m) , 4.42 (2H, t, J = 7.3 Hz), 6.55 (1H, d, J = 15.8 Hz), 7.68 (1H, d, J = 15.8 Hz), 7.79 (1H, d, J = 8.7 Hz), 7.88 (1H, d, J = 8.7 Hz), 7.92 (1H, s), 9.24 (1H, s); 13C NMR (100MHz, CD3CD) d 11.1, 23.8, 48.4, 114.3, 116.1, 120.3, 126.4, 133.8, 134.9, 135.0, 140.3, 143.5, 165.7, MS (m / z): 246 [MH] +.

Example 33 Preparation of N-hydroxy-3- (1-ethyl-2-phenethyl-1H-benzimidazole-5-iU-acrylamide (38) The title compound (38) was prepared according to the procedures described in Example 1 , using the appropriate starting materials HPLC: 99.0%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 5.06 min 1 H NMR: (400 MHz, CD30D) d 1.37 (3H, t, J = 7.3 Hz), 3.26 (2H , t, J = 7.6 Hz), 3.53 (2H, t, J = 7.5 Hz), 4.78 (2H, dd, J = 7.3 Hz), 6.60 (1H, d, J = 15.8 Hz), 7.21-7.31 (5H , m), 7.72 (1H, d, J = 15.8 Hz), 7.83-7.89 (3H, m) MS (m / z): 336 [MH] +.

Example 34 Preparation of N-hydroxy-3- (l-ethyl-lH-benzimidazol-5-yl-acrylamide (39) The title compound (39) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.86 min. 1 H NMR: (400 MHz, CD30D) d 1.64 (3 H, t, J = 7.3 Hz), 4.55 (2 H, dd, J = 7.3 Hz), 6.61 (1 H, d, J = 15.8 Hz), 7.72 (1 H, d, J = 15.8 Hz), 7.86-7.97 (3H, m), 9.38 (1H, s). MS (m / z): 232 [MH] +.

Example 35 Preparation of l- (3-hydroxy-propyl) -2-phenethyl-1H-benzimidazole-5-carboxylic acid hydroxyamide (40) The title compound (40) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 96.0%. 1 H NMR (400 MHz, CD30D, d): 1.88 (2H, m), 3.16 (2H, t, J = 7.2 Hz), 3.46 (4H, m), 4.34 (2H, t, J = 7.2 Hz), 7.12 -7.21 (5H, m), 7.82 (2H, m), 8.05 (1H, s). MS (m / z): 340 [MH] +.

Example 36 Preparation of N-hydroxy-3- [l-f2-iridin-2-yl-ethyl) -1 H-benzimidazol-5-yl-acrylamide (42) The title compound (42) was prepared according to procedures described in Example 1, using the appropriate starting materials. HPLC: 98.4%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.05 min. 1 H NMR (400 MHz, DMSO-d 6) d 3.43 (2H, t), 4.84 (2H, t), 6.53 (1H, d), 7.41 (2H, m), 7.64 (2H, m), 7.77-7.95 ( 4H, m), 8.56 (1H, s), 9.16 (1H, s). MS (m / z): 309 [MH] +.

Example 37 Preparation of -H-hydroxy-3H-ethyl-2-methyl-1H ^ (43) The title compound (43) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 96.5%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.52 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.38 (3H, t), 2.85 (3H, s), 4.42 (2H, t), 6.58 (1H, d), 7.31 (1H, m), 7.50 (lH. d), 7.88 (2H, m), 10.31 (1H, bs), 11.18 (1H, bs). MS (m / z): 246 [MH] +.

Example 38 Preparation of N-hydroxy-3-r l- (3-hydroxy-propyl) -l-benzimidazol-5-yl-acrylamide (47) The title compound (47) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: > 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.02 min. 1 H NMR (400 MHz, CD30D) d 2.12 (2 H, m), 3.58 (2 H, t, J = 5.7 Hz), 4.57 (2 H, t, J = 6.9 Hz), 6.55 (1 H, d, J = 15.8 Hz ), 7.67 (1H, d, J = 15.8 Hz), 7.79 (1H, d, J = 8.7 Hz), 7.89 (1H, d, J = 8.9 Hz), 7.92 (1H, s), 9.22 (1H, s) ); 13 C NMR (100 MHz, MeOD) d 32.7, 45.3, 59.2, 114.3, 116.1, 120.3, 126.4, 135.0. 140.3, 143.8, 165.7. MS (m / z): 262 [MH] +.

Example 39 Preparation of N-hydroxy-3- (1-methyl-2-phenethyl-1 H-benzimidazol-5-iD-acrylamide (48) The title compound (48) was prepared according to the procedures described in Example 1, using the appropriate starting materials HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 4.53 min 1 H NMR: (400 MHz, CD30D) d 3.18 (2H, t, J = 7.5 Hz), 3.47 ( 2H, t, J = 7.4 Hz), 3.76 (3H, s), 6.54 (1H, d, J = 15.8 Hz), 7.10-7.26 (5H, m), 7.65 (1H, d, J = 15.8 Hz), 7.75-7.82 (3H, m) MS (m / z): 322 [MH] +.

Example 40 Preparation of N-Mdroxy-3- (2-phenethyl-lH-benzimidazol-5-yl) -acrylamide (50) The title compound (50) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 4.36 min. 1 H NMR (400 MHz, DMSO-d 6) d 3.16 (2 H, t, J = 7.5 Hz), 3.36 (2 H, t, J = 7.9 Hz), 6.53 (1 H, d, J = 15.8 Hz), 7.17-7.29 (5H, m), 7.58 (1H, d, J = 15.8 Hz), 7.66-7.87 (3H, m). MS (m / z): 308 [MH] +.

Example 41 Preparation of N-hydroxy-3- (1H-benzimidazol-5-yl) -acrylamide (51) The title compound (51) was prepared according to the procedures described in Example 1, using the appropriate starting materials . HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 0.99 min. 1 H NMR (400 MHz, DMSO-d 6) d 6.62 (1 H, d, J = 15.8 Hz), 7.74 (1 H, d, J = 15.8 Hz), 7.85-7.99 (3 H, m), 9.32 (1 H, s) . MS (m / z): 204 [MH] +.

Example 42 Preparation of N-hydroxy-3- [l-methyl-2- (3-phenyl-propyl) -lH-benzimide-zol-5-iH-acrylamide (52) Step 1 To a previously stirred solution of trans-4 Methyl (methylamine) -3-nitrocinnamate (1.0 g, 4.0 mmol, prepared as described in Example 1) in 40 ml of methanol and 10 ml of glacial acetic acid, tin chloride (3.0 g, 16.0 g) was added. mmol). The resulting solution was heated to 55 ° C for 24 hours and then cooled to room temperature. The solvent was removed and the mixture was neutralized with sodium bicarbonate until pH = 8. The crude product was extracted with dichloromethane (20 ml) three times. The organic extracts were combined and washed twice with water (10 ml) and once with brine (10 ml) and then dried over Na2SO4 for 1 hour, filtered and concentrated. The product methyl trans-4- (methylamine) -3-aminocinnamate was obtained with a yield of 82.5% (726 mg). MS (m / z): 207 [MH] +. Step 2: 4-Phenylbutyric acid (68 mg, 0.41 mmol), methyl trans- (methylamine) -3-aminocinnamate (85 mg, 0.40 mmol) and PyBOP (236 mg, 0.46 mmol) were mixed in a round bottom container of 25 ml with 10 ml of dry dichloromethane. The resulting mixture was stirred under a nitrogen atmosphere for 5 minutes. DIEA (288 ul, 1.62 mmol) was injected and the resulting mixture was stirred at room temperature for another 4 hours. The progress of the reaction was monitored by CCD. The coupling products, methyl ester of 3- acid. { 3-amino-4- [methyl- (4-phenyl-butyryl) amino] -phenyl} Acrylic acid and 3- [4-methylamino-3- (4-phenyl-butyrylamino) -phenyl] -acrylic acid methyl ester were obtained (110 mg 78%) after purification, using column chromatography. (Solvent system: ethyl acetate: hexane = 1: 1) MS (m / z): 353 [MH] +. Step 3 The above coupling products (59 mg, 0.17 mmol) were heated with 5 ml of glacial acetic acid at 70 ° C for 4 hours. After cooling to room temperature, the pure product, 3- [1-methyl-2- (3-phenyl-propyl) -lH-benzimidazol-5-yl] -acrylic acid methyl ester, was obtained quantitatively by removing the glacial acetic acid to the vacuum 1 H NMR (400 MHz, DMSO-d 6) d 2.14 (2H, m), 2.75 (2H, t), 3.14 (2H, t), 3.95 (3H, s), 6.58 (1H, d), 7.16-7.30 ( 5H, m), 7.65 (lH.d), 7.72 (1H, d), 7.90 (2H, m). MS (m / z): 335 [MH] +. Step 4 The title compound (52) was prepared according to the procedures for preparing hydroxamic acid as described in Example 1, using the appropriate starting materials. HPLC: 99.8%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 5.01 min. 1 H NMR (400 MHz, DMSO-d 6) d 2.14 (2H, m), 2.75 (2H, t), 3.14 (2H, t), 3.95 (3H, s), 6.58 (1H, d), 7.16-7.30 ( 5H, m), 7.65 (lH.d), 7.72 (1H, d), 7.90 (2H, m), 10.89 (1H, bs) .MS (m / z): 336 [MH] +.

Example 43 Preparation of N-hydroxy-3- [l- (3-imidazol-1-yl-propyl) -2-phenethyl-1 H-benzimidazol-5-yl-1-acrylamide (56) The title compound (56) prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 98.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.50 min. 1 H NMR (400 MHz, CD30D) d 2.20 (2H, m), 3.19 (2H, m), 3.39 (2H, t, J = 7.6 Hz), 4.28 (4H, t, J = 7.6 Hz), 6.52 (1H , d, J = 16.0 Hz), 7., 17 (5H, m), 7.52 (1H, t, J = 1.5 Hz), 7.58 (1H, t, J = 1.6 Hz), 7.65 (1H, d, J = 16.0 Hz), 7.68 (2H, s), 7.85 (1H, s), 8.84 (1H, s); 13 C NMR (100 MHz, CD30D) d 29.3, 30.7, 34.4, 42.4, 47.6, 113.0. 116.2, 119.2, 121.6, 123.1, 125.7, 128.0. 129.6, 129.9, 133.7, 135.1, 136.6, 137.2, 140.7, 140.9, 156.5, 166.0. MS (m / z): 416 [MH] +.

Example 44 Preparation of N-hydroxy-3- [l- (4-dimethylamino-butyl) -2-phenethyl-1H-benzimidazol-5-yl-acrylamide (57) The title compound (57) was prepared according to procedures described in Example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.70 min. 1 H NMR (400 MHz, CD30D) d 1.71 (4H, m), 2.82 (6H, s), 3.05 (2H, t, J = 7.1 Hz), 3.21 (2H, t, J = 7.6 Hz), 3.44 (2H , t, J = 7.5 Hz), 4.27 (2H, t, J = 7.5 Hz), 6.53 (1H, d, J = 16.0 Hz), 7.20 (5H, m), 7.65 (1H, d, J = 16.0 Hz ), 7.73 (2H, m), 7.85 (1H, s); 13 C NMR (100 MHz, CD30D) d 22.8, 27.3, 29.1, 34.2, 43.5, 45.1, 58.3, 113.5, 115.6, 119.6, 125.9, 128.1, 129.5, 130.0. 134.2, 134.7, 140.4, 140.6, 156.2, 162.7, 165.9. MS (m / z): 407 [MH] +.

Example 45 Preparation of N-hydroxy-3- [l- (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazole-5-ill-acrylamide (29) Step 1: Hydrogen methyl ester of the acid 3- [ 1- (3-hydroxy-propyl) -2- isobutyl-1H-benzimidazol-5-yl] -acrylic acid (prepared according to Example 1, steps 1-3) (126.6 mg, 0.4 mmol) and Pd / C at 10% (40 mg) in 10 ml of MeOH, using a hydrogen balloon overnight. After filtering through a short column of silica gel, the filtrate was evaporated under reduced pressure to give 3- [1- (3-hydroxy-yl) -2-isobutyl-1H-benzimidazole- methyl ester. 5-yl] -propionic (127 mg) with quantitative yield: MS m / z (M + H) +: 319; 1 H NMR (400 MHz, MeOD) d 0.95 (6H, d, J = 6.4 Hz), 1.92 (2H, m), 2.19 (1H, m), 2.60 (2H, t, J = 8.0 Hz), 2.74 (2H , d, J = 7.2 Hz), 2.96 (2H, t, J = 7.6 Hz), 3.50 (2H, t, J = 4.1 Hz), 3.54 (3H, s), 4.25 (2H, t, J = 7.2 Hz ), 7.05 (1H, d, J = 8.0 Hz), 7.30-7.40 (2H, m); 13 C NMR (100 MHz, MeOD) d 20.9 (2C), 27.3, 30.1, 31.5, 34.6, 35.3, 39.5, 50.1, 57.4, 109.1, 116.4, 122.1, 132.6, 134.2, 141.3, 154.2, 173.2. Step 2 The title compound (29) was prepared according to the method previously described for the preparation of hydroxamic acid: MS m / z (M + H) +: 320; 1 H NMR (400 MHz, MeOD) d 1.00 (6H, d, J = .6.4 Hz), 2.06 (2H, m), 2.27 (1H, m), 2.42 (2H, t, J = 7.6 Hz), 3.05- 3.11 (4H, m), 3.57 (2H, t, J = 6.0 Hz), 4.52 (2H, t, J = 7.2 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.56 (1H, s), 7.78 (1H, d, J = 8.0 Hz); 13 C NMR (100 MHz, MeOD) d 20.6 (2C), 27.2, 30.4, 30.6, 32.7, 33.5, 41.5, 57.0. 112.0. 112.3, 112.4, 126.3, 129.9, 139.6, 152.3, 169.4.

Example 46 Preparation of N-hydroxy-3- [2- (benzylamino-methyl) -l-methyl-1H-benzomidazol-5-yl-1-acrylamide (60) Step 1: 3- [2-methyl] -3-methyl ester was dissolved - (N-Fmoc-aminomethyl) -l-methyl-lH-benzimidazol-5-yl] -acrylic acid (43 mg, 0.176 mmol, prepared according to Example 42, steps 1-3, using the appropriate starting materials) in 10 ml of dichloromethane. The resulting solution was treated with 2.0 ml of piperidine. Removal of all solvent and piperidine in vacuo gave 3- (2-aminomethyl-1-methyl-1H-benzimidazol-5-yl) -acrylic acid methyl ester. MS (m / z): 246 [MH] +. Step 2 Benzaldehyde (47 mg, 0.445 mmol), 3- (2-aminomethyl-1-methyl-1H-benzimidazol-5-yl) -acrylic acid methyl ester (109 mg, 80%, 0.445 mmol) and acid were dissolved. acetic acid (27 mg, 0.445 mmol) in 15 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (142 mg, 95%, 0.668 mmol) was added to the above solution. The reaction was completed after 12 hours and the organic layer was washed twice with saturated NaHCO 3 (10 ml), followed by washing twice with water (10 ml), once with brine (10 ml) and then drying over Na2S04. After filtration, the crude product was obtained (100 mg, 67.6% yield), 3- [2- (benzylamino-methyl) -l-methyl-1H-benzimidazol-5-yl] -acrylic acid methyl ester, eliminating the solvent MS (m / z): 336 [MH] +. Step 3 The title compound (60) was prepared according to the procedures described in Step 4 of Example 1, using 3- [2- (benzylamino-methyl) -l-methyl-1H-benzimidazole methyl ester. -il] -acrylic as starting material. HPLC: 89.6%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.68 min. 1 H NMR (400 MHz, DMSO-d 6) d 3.78 (3 H, s), 4.37 (2 H, s), 4.58 (2 H, s), 6.48 (1 H, d), 7.46 (3 H, m), 7.55 (3 H, m) 7.64 (2H, t) 7.88 (1H, s), 9.88 (1H, bs), 10.74 (1H, bs). MS (m / z): 337 [MH] +.

Example 47 Preparation of N-hydroxy-3-f l- (3-dimethylamino-propyl) -2-phenethyl-1 H-benzimidazol-5-yl] -acrylamide (63) The title compound (63) was prepared in accordance with the procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.52 min. 1 H NMR (400 MHz, DMSO-d 6) d 2.09 (2H, m), 2.75 (3H, s), 2.76 (3H, s), 3.12-3.22 (4H, m), 3.37 (2H, b), 4.50 ( 2H, b), 6.55 (1H, d, J = 15.76 Hz), 7.22-7.34 (5H, m), 7.63 (1H, d, J = 15.76 Hz), 7.66 (1H, d, J = 7.80 Hz), 7.82 (1H, d, 7.80 Hz), 7.92 (1H, s). MS (m / z): 393 [MH] +.

Example 48 Preparation of N-hydroxy-3-r2- (benzylamino-methyl-Vethyl-lH-benzimidazole-5-yl-acrylamide (64) The title compound (64) was prepared according to the procedures described in Example 46 , using the appropriate starting materials HPLC: 98.5%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 3.52 min 1 H NMR (400 MHz, DMSO-d6) d 1.31 (3H, t) 3.37 (2H, m) , 3.50 (2H, t), 4.28 (4H, m), 6.48 (1H, d), 7.43-50 (3H, m), 7.55 (3H, m) 7.73-7.83 (2H, t) 7.95 (1H, s ), 9.25 (1H, bs), 10.76 (1H, bs), MS (m / z): 351 [MH] +.

Example 49 Preparation of N-hydroxy-3- (2- (benzyl-l-methyl-3-oxo-lH-benzimida-zol-5-yl) -acrylamide (65) The title compound (65) was prepared from according to the procedures described in Example 42, using the appropriate starting materials HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, 5-65% gradient B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 4.48 min 1 H NMR (400 MHz, DMSO-d6) d 3.87 (3H, s ), 4.59 (2H, s), 6.57 (1H, d, J = 15.9 Hz), 7.09-7.36 (5H, m), 7.62 (1H, d, J = 15.8 Hz), 7.73-7.95 (3H, m) MS (m / z): 309 [MH] +.

Example 50 Preparation of N-hydroxy-3-t "1- (2-diethylamino-ethyl) -2-phenethyl-1H-benzyl-midazole-5-ill-acrylamide (66) The title compound (66) was prepared from according to the procedures described in Example 1, using the appropriate starting materials HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% of B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid, UV 254): 3.72 min 1 H NMR (400 MHz, CD30D) d 1.29 (6H, t, J = 7.3 Hz), 3.26 (8H, m), 3.40 (2H, t, J = 7.5 Hz), 4.60 (2H, t, J = 8.0 Hz), 6.50 (1H, d, J = 16.0 Hz), 7.21 ( 5H, m), 7.62 (1H, d, J = 16.0 Hz), 7.70 (2H, m), 7.85 (1H, s), 13C NMR (100 MHz, CD30D) d 9.0, 29.4, 34.3, 39.9, 48.4, 50.3, 112.7, 116.6, 119.3, 125.8, 128.1, 129.6, 130.0, 133.9, 134.9, 137.6, 140.8, 157.0, 166.0, MS (m / z): 407 [MH] +.

Example 51 Preparation of N-hydroxy-3-r2-phenethyl-1- (piperidin-1-yl-ethyl) -lH-benzimidazole-5-yl-acrylamide (67) The title compound (67) was prepared from according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.90 min. 1 H NMR (400 MHz, CD30D) d 1.86 (6H, br s), 3.26 (8H, m), 3.40 (2H, t, J = 7.5 Hz), 4.62 (2H, t, J = 7.9 Hz), 6.50 ( 1H, d, J = 16.0 Hz), 7.23 (5H, m), 7.62 (1H, d, J = 16.0 Hz), 7.70 (2H), 7.84 (1H, s); 13 C NMR (100 MHz, CD30D) d 22.5, 24.2, 29.4, 34.3, 39.6, 54.4, 54.9, 112.7, 116.6, 119.2, 125.7, 128.1, 129.6, 130.0. 133.8, 134.9, 137.8, 140.8, 157.0. 166.0. MS (m / z): 419 [MH] +.

Example 52 Preparation of N-hydroxy-3-r2-phenethyl-1- (2-pyrrolidin-1-yl-ethyl) -lH-benzimidazol-5-yl-acrylamide (72) The title compound (72) was prepared, according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.71 min. 1 H NMR (400 MHz, CD30D) d 2.06 (4H, br), 3.21 (2H, t, J = 7.4 Hz), 3.26 (4H, m), 3.37 (2H, t, J = 7.7 Hz), 3.42 (2H , t, J = 7.5 Hz), 4.57 (2H, t, J = 7.4 Hz), 6.47 (1H, d, J = 16.0 Hz), 7.21 (5H, m), 7.58 (1H, d, J = 16.0 Hz ), 7.67 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.83 (1H, s); 13 C NMR (100 MHz, CD30D) d 24.1, 29.4, 34.3, 41.1, 52.8, 55.7, 112.9, 116.5, 119.2, 125.8, 128.1, 129.6, 130.0. 133.9, 134.9, 137.2, 140.7, 140.8, 157.0. 165.9. MS (m / z): 405 [MH] +.

Example 53 Preparation of N-hydroxy-3-r2- (2-benzylamino-ethyl) -l-ethyl-1 H-benzymidazol-5-yl-1-acrylamide (74) The title compound (74) was prepared in accordance with the procedures described in Example 46, using the appropriate starting materials. HPLC: 98.5%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 3.52 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.31 (3 H, t) 3.37 (2 H, m), 3.50 (2 H, t), 4.28 (4 H, m), 6.48 (1 H, d), 7.43-50 (3 H , m), 7.55 (3H, m) 7.73-7.83 (2H, t) 7.95 (1H, s), 9.25 (1H, bs), 10.76 (1H, bs). MS (m / z): 365 [MH] +.

Example 54 Preparation of N-hydroxy-3- [2-phenethyl-1- (3-pyrrolidin-1-yl-propyl) -l-benzimidazole-5-yl and acrylamide (82) The title compound (82) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna column C18 2.0 x 150 mm 5μ; 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.18 min. 1 H NMR (400 MHz, CD30D) d 2.01 (2H), 2.17 (4H), 3.03 (2H), 3.26 (4H), 3.48 (2H), 3.62 (2H), 4.37 (2H), 6.60 (1H), 7.27 . (5H), 7.71 (1H), 7.78 (2H), 7.91 (1H). MS (m / z): 419 [MH] +. Example 55 Preparation of N-hydroxy-3-ri- (3-dimethylamino-2,2-dimethyl-propyl) -2- (2-pyridin-3-yl-ethyl) -l H-benzimidazol-5-yl] -acrylamide (86) The title compound (86) was prepared according to the procedures described in Example 42, using the appropriate starting materials. HPLC: 90.4%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.24 min. 1 HOUR NMR (400 MHz, DMSO-d6) d 1.00 (6H, s), 2.94 (6H, s), 3.32 (2H, m), 3.38 (4H, m) 4.35 (2H, m), 6.52 (1H, d) ), 7.58-7.86 (5H, m) 8.20 (1H, d), 8.65 (1H, m) 8.77 (1H, s), 9.50 (1H, s). MS (m / z): 422 [MH] +.

Example 56 Preparation of 2-r2-phenethyl-1- (3A5-trimethoxy-benzyl) -1 H-benzimidazole-5-yl-cyclopropanecarboxylic acid hydroxyamide Step 1 To a solution of (CH3) 3S (0) I (132 mg, 0.6 mmol) in anhydrous DMSO (1 ml) was added sodium hydride (28 mg, 60% in mineral oil) at room temperature under nitrogen gas, then a solution of the compound (244 mg, 0.5 mg) was added. mmol), 3- [2-phenethyl- (3,4,5-trimethoxy-benzyl) -lH-benzimidazol-5-yl] -acrylic acid methyl ester (prepared according to Example 1, steps 1 3), in 4 ml of anhydrous THF at the end of minutes. The resulting mixture was then stirred at room temperature overnight. After aqueous workup, the residue was obtained as an oil (135 mg), which was then subjected to the next step without further purification. Step 2 To a solution of the above crude product in 0.5 ml of MeOH was added a stock solution of NH20H 2.0 M previously prepared as we did previously (2 ml). The resulting mixture was stirred at room temperature for 4 h. After neutralizing with TFA (0.4 ml), the resulting mixture was subjected to HPLC purification to obtain 10 mg of the desired compound shown in title (88). HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 6.36 min. 1 H NMR (400 MHz, CD30D) d 1.21-1.29 (1H, m), 1.45-1.52 (1H, m), 1.75-1.79 (1H, m), 2.48-2.55 (1H, m), 2.99 (2H, t , J = 8.0 Hz), 3.45 (2H, t, J = 8.0 Hz), 3.61 (6H, s), 3.64 (3H, s), 5.42 (2H, s), 6.40 (2H, s), 7.00-7.18 (5H, m), 7.26 (1H, d, J = 8.4 Hz), 7.45 (1H, s), 7.59 (1H, d, J = 8.4 Hz). MS (m / z): 502 [MH] +.

Example 57 Preparation of N-hydroxy-3-r 2 -benzylsulfanyl-1- (3-dimethylamino-2-dimethyl-propyl) -l H-benzimidazol-5-yl-1-acrylamide (89) Step 1: Acid 3 was mixed [4A (3-dimethylamino-2,2-dimethyl-propylamino) -3-nitro-phenyl] -acrylic acid (1.93 g, 6.0 mmol, prepared as described in Example 1, step 1), tin chloride (13.5 g, 60 mmol) and MeOH (50 ml) and heated at 45 ° C for 20 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. To the residue were added 100 ml of dichloromethane and 100 ml of water. The pH was adjusted to 10 with concentrated ammonia. The layers were separated and the aqueous phase was extracted with 100 ml of dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. To the resulting residue was added MeOH (100 ml), CS2 (18 ml) and potassium hydroxide (3.4 g). The reaction mixture was heated at 80 ° C for 16 hours, then cooled to room temperature and the solvents were removed under reduced pressure. The resulting crude product was recrystallized from MeOH. The product, 3- [l- (3-dimethylamino-2,2-dimethyl-propyl) -2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl] -acrylic acid, was obtained with a yield of 75% in two stages (1.5 g). MS (m / z): 334 [MH] +. Step 2: 3- [l- (3-Dimethylammo-2,2-dimethyl-propyl) -2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl] -acrylic acid was mixed (100 mg, 0.3 mmol), benzyl bromide (360 mg, 3.6 mmol) and potassium carbonate (0.83 g) with 10 ml of DMF. The resulting mixture was stirred overnight at 45 ° C. The desired product, benzyl ester of 3 - [2-benzylsulfanyl- l- (3-dimethylamino-2,2-dimethyl-propyl) -2,3-dihydro- 1H-benzimidazol-5-yl] -acrylic acid, was purified by preparative HPLC: 150 mg (76.6% yield). 1 H NMR (400 MHz, DMSO-d 6) d 1.08 (6H, s), 2.88 (3H, s), 2.89 (3H, s), 3.30 (2H), 4.11 (2H, s), 4.65 (2H, s). , 5.24 (2H, s), 6.72 (2H, d, J = 15.96 Hz), 7.26-7.47 (10H, m), 7.68 (2H, bs), 7.83. (1H, d, J = 15.96 Hz), 8.00 (1H, s). MS (m / z): 514 [MH] +. Step 3: The title compound (89) was obtained by treatment of 3- [2-benzylsulfanyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -2,3-dihydro-1H-benzimidazole benzyl ester. -5-yl] -acrylic according to the previously described method for the preparation of hydroxamic acid (Step 4 of Example 1). HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.87 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.09 (6H, s), 2.88 (3H, s), 2.89 (3H, s), 3.26 (2H), 4.11 (2H, s), 4.65 (2H, s) , 6.48 (2H, d, J = 15.79 Hz), 7.26-7.47 (6H, m), 7.58 (1H, d, J = 15.79 Hz), 7.65 (1H, d, J = 8.48 Hz), 7.80 (1H, s). MS (m / z): 439 [MH] +.

Example 58 Preparation of N-hydroxy-3-rl- (3-dimethylamino-2,2-dimethyl-propyl) -2-phenylmethanesulfonyl-1H-benzimidazol-5-yl] -acrylamide (91) Step 1 118 mg of ester were mixed 3- [2-benzylsulfanyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -2,3-dihydro-1H-benzimidazol-5-yl] -acrylic acid benzyl acid (prepared according to Example 57 , steps 1-2), 1.0 ml of hydrogen peroxide (30%) and 10 ml of acetic acid at 0 ° C in an ice bath. Without adding additional ice, the reaction mixture was stirred overnight. The product, 3- [1- (3-dimethylamino-2,2-dimethyl-pro? Il) -2-phenylmethanesulfinyl-2,3-hydro-1H-benzimidazol-5-yl] -acrylic acid benzyl ester, is obtained in a quantitative way. MS (m / z): 530 [MH] +. Step 2 The title compound (91) was obtained by treatment of 3- [1- (3-dimethylamino-2,2-dimethyl-propyl) -2-phenylmethanesulfinyl-2,3-hydro-1H-benzimidazole benzyl ester. -5-yl] -acrylic according to the previously described method for the preparation of hydroxamic acid (Step 4 of Example 1). HPLC: 77.1%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.46 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.11 (6H, s), 2.90 (3H, s), 2.91 (3H, s), 3.12 (2H, s), 3.82 (2H, s), 4.79 (2H, s), 6.56 (1H, d, J = 15.80 Hz), 7.15-7.32 (5H, m), 7.59-7.66 (2H, m), 7.87 (1H, d, J = 8.68 Hz), 8.06 (1H, s ). MS (m / z): 455 [MH] +.

Example 59 Preparation of N-hydroxy-3- (2-benzyl-1-ethyl-1H-benzimidazol-5-yl) -acrylamide (92) The title compound (92) was prepared according to the procedures described in Example 42, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.60 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.17 (3 H, t, J = 7.1 Hz), 4.34 (2 H, dd, J = 6.8 Hz), 4.56 (2 H, s), 6.55 (1 H, d, J = 15.8 Hz), 7.31-7.40 (5H, m), 7.63 (1H, d, J = 15.8 Hz), 7.85-7.93 (3H, m). MS (m / z): 322 [MH] +.

Example 60 Preparation of N-hydroxy-3-yl-ethyl-2-r3- (lH-indol-3-yl) -propyl-1-lH-benzimidazol-5-yl) -acrylamide (93) The title compound (93 ) was prepared according to the procedures described in Example 42, using the appropriate starting materials. HPLC: 98.5%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.98 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.33 (3H, t), 2.22 (2H, m), 2.87 (2H, t), 3.16 (2H, m), 4.37 (2H, m), 6.53 (1H, d), 6.98 (1H, m) 7.06 (1H, m) 7.19 (1H, s), 7.33 (lH.d), 7.54-7.88 (5H, d), 10.82 (2H, bs). MS (m / z): 389 [MH] +.

Example 61 Preparation of N-hydroxy-3-yl- (3-dimethylamino-2,2-dimethyl-propyl) -2- [2- (3-methoxy-phenyl-V-ethyl-1-lH-benzimidazol-5-yl) -acrylamide (94 The title compound (94) was prepared according to the procedures described in Example 42, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.34 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.03 (6H, s), 2.90 (6H, s), 3.19 (2H, t), 3.34 (4H, s) 3.71 (3H, s) 4.29 (2H, t) , 6.52 (1H, d), 6.80 (1H, m) 6.88 (2H, d) 7.22 (1H, m), 7.62 (2H.m), 7.83-7.89 (2H, m), 9.34 (1H, s), 10.77 (1H, bs). MS (m / z): 451 [MH] +.

Example 62 Preparation of N-hydroxy-3- [l-ethyl-2- (3-phenoxy-propyl) -l H-benzimide-zol-5-yl-acrylamide (96) The title compound (96) was prepared from according to the procedures described in Example 46, using the appropriate starting materials. HPLC: 99.6%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.83 min. 1 H NMR (400 MHz, DMSO-d 6) d 1.36 (3H, t), 2.32 (2H, m), 3.34 (2H, m), 4.12 (2H, m), 4.46 (2H, m), 6.58 (1H, d), 6.73 (2H, d) 6.90 (1H, m) 7.22 (2H, m), 7.65 (1H, d), 7.80 (1H, d), 7.94 (2H, m). MS (m / z): 366 [MH] +.

Example 63 Preparation of N-hydroxy-3- (2-ir2- (4-methoxy-phenyl) -acetylamino-1-methyl) -l-methyl-H-benzimidazol-5-yl) -acrylamide (99) The title compound ( 99) was prepared according to the procedures described in Example 42, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 2.75 min. 1 H NMR (400 MHz, DMSO-d 6) d 3.48 (2H, s), 3.67 (3H, s), 3.87 (3H, s), 4.71 (2H, m), 6.55 (1H, d), 6.86 (3H, m) 7.18 (3H, m) 7.84-7.92 (2H, m), 10.77 (1H, s). MS (m / z): 395 [MH] +.

Example 64 Preparation of 2- (1-methyl-2-phenethyl-1H-benz-midazol-5-yl) -cyclopropanecarboxylic acid hydroxyamide (100) The title compound (100) was prepared according to the procedures described in Example 56, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 6.36 min 1 H NMR (400 MHz, CDCB, with one drop of d6-DMSO-d6) d 1.25 (1H, m), 1.64 (1H, m), 1.88 (1H, m) , 1.98 (3H, s), 2.63 (1H, m), 3.23 (2H, t, J = 8.0 Hz), 3.52 (2H, t, J = 8.0 Hz), 7.08-7.45 (7H, m), 7.57 ( 1H, s). MS (m / z): 336 [MH] +.

Example 65 Preparation of N-Mdroxy-3- (1-methyl-1H-benzimidazol-5-yl) -acrylamide (49) The title compound (49) was prepared according to the procedures described in Example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 x 150 mm 5μ column, 0.8 ml / min, gradient 5-65% B for 15.5 min, solvent A: H20 with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1 % trifluoroacetic acid, UV 254): 1.05 min. 1 H NMR: (400 MHz, CD30D) d 4.05 (3H, s), 6.52 (1H, d, J = 15.8 Hz), 7.62 (1H, d, J = 15.8 Hz), 7.77-7.89 (3H, m), 9.19 (1H, s). MS (m / z): 218 [MH] +. The following compounds are some representative examples prepared by means of methods described or analogous to those described in Examples 1-65 above: Table 1 Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 1 (continued) By means of methods analogous to those described above, a wide variety of compounds of the formula I could be prepared, including, but not limited to, those of Table 2 (a): Table 2 (a) Table 2 (a) (continued) Table 2 (a) (continued) By means of methods analogous to those described above and by varying the starting materials used in the synthesis, a wide variety of compounds of the formula I could be prepared, including, but not limited to, those of Table 2 (b): Table 2 (b) Table 2 (b) (continued) Rl R2 R3 R4 X Y 127 Propyl or CH3 H N02 CF3 y ^ A "128 Propyl A = C, N,?, S H CH3 CH3 CN 129 Propyl \ '' CH3 CH3 OCH3 OCF3 130 Propyl í ° / r-y H H N02 131 Propyl "" N ^^ and CH3 H CH3 CH3 132 H CH3 OCH3 OCH3 133 o.T CH3 CH3 H 134 o H H CH3 N. 135 1 N CH3 H OCH3 Cl A ^ 136 A = C, N,?, S H CH3 Br 137 CH3 CH3 CH3 CH3 Table 2 (b) (continued) Table 2 (b) (continued) Table 2 (b) (continued) Rl R2 R3 R4 X Y ** 161 A = C, N,?, S CH3 CH3 Cl CH3 162 A = C, N,?, S H H Br H 163 CH3 H CH3 -N 164 -M H CH3 OCH3 Cl .s 165 W // CH3 CH3 CF3 Br .N. 166 H H CN CH3 167 o CH3 H OCF3 OCH3 168 H CH3 N02 CF3 ? 169 // CH3 CH3 CH3 CN 170 H H OCH3 OCF3 N 171 CH3 H N02 172 H CH3 CH3 CH3 Table 2 (b) (continued) Table 2 (b) (continued) Table 2 (b) (continued) Table 2 (b) (continued) Table 2 (b) (continued) Table 2 (b) (continued) Biological tests and enzyme assays Expression and purification of recombinant GST-HDAC1 A human cDNA library was prepared with cultured SW620 cells. The amplification of the coding region of human HDAC1 and HDAC8 from this cDNA library was cloned separately into the baculovirus expression of the pDEST20 vector and the pFASTBAC vector, respectively (GATEWAY Cloning Technology, Invitrogen Pte Ltd). The pDEST20-HDACl and pFASTBAC-HTGST-HDAC8 constructs were confirmed by determination of the DNA sequences. The recombinant baculovirus was prepared by the Bac-To-Bac method, according to the manufacturer's instructions (Invitrogen Pte Ltd). The Baculovirus titer was determined by plaque assay at approximately 108 PFU / ml. Expression of GST-HDAC1 or HTGST-HDAC8 was performed by infection of SF9 cells (Invitrogen Pte Ltd) with baculovirus pDEST20-HDAC1 or pFASTBAC-GST-HDAC8 at MOI = 1 for 48 h. The soluble cell lysate was incubated with pre-equilibrated beads of Glutathione Sepharose 4B (Amersham) at 4 ° C for 2 h. The beads were washed 3 times with PBS buffer. The GST-HDAC1 protein or the GST-HDAC8 protein were eluted by elution buffer containing 50 mM Tris, pH 8.0. 150mM NaCl, 1% Triton X-100 and reduced glutathione lOmM or 20mM. The purified GST-HDAC1 protein or the purified GST-HDAC8 protein was dialyzed with HDAC storage buffer containing 10 mM Tris, pH 7.5, 100 mM NaCl and 3mM MgC12. 20% glycerol was added to the purified GST-HDAC1 protein or the purified GST-HDAC8 protein before storage at -8O0C.

In vitro HDAC assay for the determination of IC 50 values The assay was carried out in 96-well format and the HDAC activity assay based on BIOMOL fluorescence was applied. The reaction mixture comprised of assay buffer, containing 25 mM Tris, pH 7.5, 137 mM NaCl, 2.7 mM KCl, 1 mM MgC12, 1 mg / ml BSA, test compounds, 500 nM HDAC8 enzyme or HDAC1 enzyme 600 nM, peptide substrate Flur de lys p53 200 μM for HDAC8 enzyme or generic substrate Flur de lys 500 μM for enzyme HDAC1, and then incubated at room temperature for 2 h. Flur de lys desenanollador was added and the reaction mixture was incubated for 10 min. Briefly, the deacetylation of the substrate sensitizes it to the unwinder, which then generates a fluorophore (symbol). The fluorophore is excited with the light of 360 nm and the emitted light (460 nm) is detected by a fluorometric plate reader (detection system Tecan Ultra Microplate, Tecan Group Ltd.). Prism 3.0 analytical software was used to generate IC50 from a series of data. The results of the inhibition of the HDAC enzyme by the representative compounds are shown in Table 3.

Table 3 Table 3 (continued) Table 3 (continued) Table 3 (continued) Compound Activity Enzymatic enzyme activity of HDAC1 IC50 HDAC8 IC50 (μM) (μM) 58 1.14 59 0.382 60 0.116 61 0.196 62 0.234 63 0.162 64 0.230 65 0.062 66 0.072 0.255 67 0.039 0.254 68 0.294 69 0.146 70 0.923 71 0.167 72 0.052 73 0.560 74 0.371 75 0.290 76 1.03 Table 3 (continued) ) Table 3 (continued) Cell-based proliferation assay for the determination of GI50 values Human colon cancer cell lines (Colo205 and HCT116), human breast cancer cell lines (MDA-MB435 and MDA-MB231) and cancer cell line were obtained. human lung (A549) from ATCC. Colo205 cells were cultured in RPMl 1640 containing 2 mM L-glutamine, 5% FBS, 1.0 mM Na pyruvate. A549 and MDA-MB231 were grown in RPMl 1640 containing 2 mM L-glutamine, 5% FBS. The MDA-MB435 cells were cultured in DMEM containing 2 mM L-glutamine, 5% FBS. HCT116 cells were cultured in IMEM containing 2 mM L-glutamine, 5% FBS. The A549 and Colo205 cells were plated in 96-well plates with 2,000 and 5,000 cells per well, respectively. The MDA-MB435, HCT116, MDA-MB231 cells were plated in 96-well plates with 6,000 cells per well. The plates were incubated at 37 ° C, 5% C02, for 24 h. The cells were treated with compounds with different concentrations for 96 h. Cell growth was then monitored by a quantitative cell proliferation assay (Invitrogen Pte Ltd). The dose response curves were graded to determine the GI50 values for the compounds by XL adjustment. The results of cellular activity of the representative compounds are shown in Table 4. Table 5 summarizes the antiproliferative activities of selected compounds, including their different salts, for other cancer cell lines. These data indicate that the compounds of this invention are very active in inhibiting the growth of tumor cells.

Table 4 Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 5 Table 5 (continued) Histone H3 Acetylation Assay A characteristic of histone deacetylase inhibition (HDAC) is the increase in the level of acetylation of histones. Acetylation of histone, for example H3, H4 and H2A, can be detected by immunostaining (western blot). Colo205 cells, approximately 1.5 x 106 cells / 10 cm dish, were seeded in the medium described above, cultured for 24 h and then treated with HDAC inhibitors with 0.1, 1, 5 and 10 μM final concentration. After 24 h the cells were harvested and lysed according to the instructions of Sigma Mammalian Cell Lysis Kit. The protein concentration was quantified by the BCA method (Sigma Pte Ltd). The protein lysate was separated by 4-12% bis-tris gel SDS-PAGE (Invitrogen Pte Ltd) and transferred to a PVDF membrane (BioRad Pte Ltd). A probe was applied separately to the membrane by primary antibody specific for acetylated H3, Acetylated H4 or acetylated H2A (Upstate Pte Ltd). The detection antibody, goat anti-rabbit antibody conjugated with HRP, was used according to the manufacturer's instructions (Pierce Pte Ltd). After extracting the membrane detection antibody, a substrate with enhanced chemiluminescence for the detection of HRP was added to the membrane (Pierce Pte Ltd). After extracting the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 s - 20 min. The X-ray film was unfolded by the X-ray film processor. The density of each band observed in the slatted film could be analyzed by UVP Bioimaging software (UVP, Inc., Upland, CA). The values against the actin density were then normalized in the corresponding samples, in order to obtain the expression of the protein. The results of the immunostaining assay (immunoblotting) by antibodies against histone deacetylase H3, H4 and H2A are shown in Table 6.

Table 6 These data demonstrate that the compounds of this invention inhibit histone deacetylases, whereby an accumulation of acetylated histones is obtained.

Histone H3 Acetylation Assay - ELISA Approach An enzyme-linked immunosorbent assay (ELISA) can be applied to detect and quantify acetylated histone 3 (AcH3) in the protein lysate obtained from the cancer cell lines treated with HDAC inhibitors. . The ELISA assay was deannolled to detect the level of AcH3 from the colo205 colon cancer cell line treated with the HDAC inhibitor compounds 10 μM HDAC. The protein lysates from treated and untreated Colo205 were obtained as described above. The protein concentration from the lysed cells was determined by the BCA method (Sigma-Aldrich Pte Ltd).

Different combinations of antibodies (see Table 7) that could be used as a primary antibody (capture antibody) or secondary antibody were investigated in order to determine the appropriate antibodies, in addition to optimizing antibody concentrations and assay conditions. It was found that combinations of murine monoclonal antibody against H3 and rabbit polyclonal antibody against AcH3 (Lys9 / 14) produced the best antigen binding, whether peptides or lysed proteins from the colo205 colon cancer cell line treated with the HDAC inhibitors. No background values were observed. The detection antibody used in this ELISA test was anti-rabbit antibody of buno conjugated with peroxidase. In order to determine EC50 when acetylated histone 3 was induced by 50%, Colo205 cells were cultured in a 96-well plate with 1.5 x 10 5 cells / well for 24 h. The Colo205 cells were then treated with HDAC inhibitors in different doses (in duplicate, in treatment with 9 doses, in dilutions to the quarter from 100 μM). After treating them for 24 h, the cells were lysed and the protein concentration was determined. The ELISA plate (inmulon 2HB plate, Biolaboratories Pte Ltd) was coated with 4 μg / ml of murine monoclonal antibody against H3 at 4 ° C overnight. After extracting the murine monoclonal antibody against H3, the plate was washed with PBS buffer containing 0.05% Tween-20 and blocked with superblock solution (Pierce Pte Ltd) at 37oC, 1 h. The superblock solution was removed and the plate was washed with PBS buffer containing 0.05% Tween. The AcH3 peptide, the H3 peptide and the protein lysates from the Colo205 cells treated with the HDAC inhibitors were applied. The capture reaction was carried out between the primary antibody and the antigen, which is histone 3 in the samples, at 37 ° C for 1 h. After extracting the samples, the plate was washed with PBS buffer containing 0.05% Tween. The secondary antibody, 0.5 μg / ml rabbit polyclonal antibody against AcH3 (Lys9 / 14), was applied to detect the acetylation of H3 in the samples at 37oC for 1 h. After extracting secondary antibodies, the plate was washed with PBS buffer containing 0.05% Tween. The detection antibody was applied to detect the secondary antibody that captured AcH3 in the samples at 37 ° C for 30 min. The substrate, 1-step Turbo TMB (Pierce Pte Ltd) was applied for 30 min until color development. The reaction was stopped by 1M H2SO4. The absorbance at OD 450 nm was measured with a Spectromax reader (Molecular Devices Corporation, Sunnivale, CA). The standard curve was plotted and the concentration of AcH3 [(Lys9 / 14), μg / ml] in a sample using the Softmax software from Spectromax. The amount of AcH3 in a sample was calculated based on the following formula; pg of AcH3 (Lys9 / 14) / μg of total protein = (μs of AcH3 (Lvs9 / 14) in the test *) *! 06 μg of protein in the assay The dose-response curves were graded to determine the EC50 values for the compounds with XL-fit adjustment (ID Business Solution, Emeryville, CA). [Table 8] Table 7: Antibodies used in the cross-species cross-reactivity test and in the combined antibody studies Table 8 presents data for the selected compounds, as the effective concentration for the induction of histone 3 acetylation ([AcH3 (Lys9 / 14)]) as a 50% signal (EC50).

Table 8 Antineoplastic effect in vivo (or antitumor) of the HDAC inhibitors: In data not shown selected compounds were analyzed with the maximum tolerated dose in normal mice, and were found to be well tolerated by the mice, without signs of toxicity or side effects in the applied dose range (which can be> 200 mg / kg / day). The efficacy of the compounds of the invention can then be determined by xenograft studies in vivo in animals. In these studies, subcutaneous implants were made on the flank of nude nude mice (Harian) females 12-14 weeks of age, with 5 x 10 6 cells of human colon carcinoma HCT116 or with 1 x 106 cells of human colon carcinoma Colo205 suspended in 50% of Matrigel. When the tumor reached a size of 100 mm3, nude mice were mated with xenograft in various treatment groups. The selected HDAC inhibitors were dissolved in suitable vehicles, such as 10% DMA / 10% Cremophore / 80% water and administered intraperitoneally in nude mice with xenograft daily for 14 days. The volume of the dose was 0.2-ml / 20g of mouse. Paclitaxol was used as a positive control, prepared for intravenous administration in 10% ethanol / 10% Cremo? Hore / 80% water. The dose volume for Paclitaxol was 0.015-ml / g of mouse. The volume of the tumor was calculated every other day after the injection, by the formula: Tumor volume (mm3) = (w2 x l) / 2, where w = width and 1 = length in mm of an HCT116 or Colo205 carcinoma. The compounds of this invention studied showed significant reduction in tumor volume compared to controls treated only with the vehicle. The activity of histone deacetylase should be reduced when measured, and there is accumulation of acetylated histone, relative to the control group treated with the vehicle. The details of the specific embodiments described in this invention should not be construed as limitations. Various equivalents and modifications can be made without departing from the spirit and scope of the invention and it is understood that said equivalent embodiments are part of this invention.

Claims (5)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore, the content of the following is claimed as property: CLAIMS 1) A compound of the formula (I): characterized in that: R1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl , heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl , alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR4 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR5 , -COR5, -SH, -SR6, -OR6 and acyl; or Rl = L; R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR5 and acyl, each of which may be unsubstituted or substituted by one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, - N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (0) OR5, -SH, - SR5, -OR6 and acyl; or R2 = L; R3 is selected from the group consisting of H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino , aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (0) OR5, -COR5, -SH, -SR6, -OR6, acyl and -NR7R8; each R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R7 and R8 are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-Ll-W ~ wherein Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or several substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl , arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (0) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl. Ll is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = 0; = S; -CN; -N02; alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) -N (R10) -; b) L = Cy-Ll-W-L2 wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected in a manner independent of the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl , arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (0) OR 5, -COR 5, -SH, -SR 5, -OR 6 and acyl; Ll and L2 are the same or different and are, independently, C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; ~ CF3, -OCF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0> - N (R10) -; c) L = Cy- (CH2) mW- wherein, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen, = 0, = S, -CN, -N02, -CF3, -0CF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, -amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR 5, -COR 5, -SH, -SR 5, -OR 6 and acyl; m is 0, 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) -, -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0> -N (R10) -; d) L = L1- W-L2 Ll and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = 0; = S; -CN; -N02; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (0) 2-, -N (R9) -, -C (0) N (R9) - -S02N (R9) -, N (R9) C (0) -, N (R9) S02- and -N (R9) -C (0) - N (R10) -; R9 and RIO are the same or different and are independently selected from H, C1-C6 alkyl, C-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl; Z is a single bond or is selected from -CH2-, -CH2CH2-, -CH = CH-, C3-C6 cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl; or one of its pharmaceutically acceptable salts. 2) A compound according to claim 1, characterized in that: Z is a bond, -CH2-, -CH2CH2- or -CH = CH-, C3-C6 cycloalkyl and Z is attached at the position of ring 5 or 6. 3) A compound according to claim 1 or 2, characterized in that: Z is -CH = CH- and is attached at the position of the ring 5. 4) A compound according to any of claims 1 to 3, characterized in that : R3 = H. 5) A compound according to any of claims 1 to 4, characterized in that: X and Y = H. 6) A compound according to any of claims 1 to 5, characterized in that: R4 = H. The compound according to any of claims 1 to 6, characterized in that: R1 is selected from the group consisting of: H, hydroxyalkyl, alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aminoalkyl and heterocycloalkyl, each of which it may be unsubstituted or substituted. 8) The compound according to any of claims 1 to 7, characterized in that: Rl is selected from the group consisting of: H; methyl; (pyridin-2-yl) methyl; (pyridin-3-yl) methyl; ethyl; 2-hydroxy-ethyl; 2- (pyridin-2-yl) ethyl; 2- (pyridin-3-yl) ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2- (morpholinyl) ethyl; 2- (piperidin-1-yl) -ethyl; 2- (pyrrolidin-1-yl) -ethyl; 2-diethylamino-ethyl; propyl; 2,3-di-hydroxy-propyl; 3-hydroxypropyl; 3-methoxypropyl; 3-isopropoxy-ropyle; 2,2-dimethylpropyl; 3-dimethylamino- or propyl; 3-dimethylamino-2,2-dimethyl-propyl; 3- (2-oxo-pinolidin-1-yl) -propyl; 3- (morpholin-4-yl) -propyl; 3- (imadazol-1-yl) -propyl; 3- (4-methyl-piperidin-1-yl) -propyl; 3- (pinolidin-1-yl) -propyl; - dimethylamino-butyl; 5-hydroxy-pentyl; allyl; benzyl; 3,4,5-trimethoxybenzyl. 9) A compound according to any of claims 1 to 8, characterized in that: R 2 is selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, each of which may be unsubstituted or substituted. 5 10). A compound according to any of the claims

1 to 9, characterized in that: R2 is H; methyl; benzylamino-methyl; dibenzylamino-methyl; [2- (4-fluoro-phenyl) -acetylamino] -methyl; [2- (4-methoxy-phenyl) -acetylamino] -methyl; 4-methoxy-benzylamino-methyl; benzyloxy-methyl; phenylacetylamino-0 methyl; l-amino-2-phenyl-ethyl; 2-benzylamino-ethyl; 2- (3-methoxy-phenyl) -ethyl; 2- (pyridin-3-yl) ethyl; 2- (2-phenoxyacetylamino) -ethyl; 2- benzenesulfonylamino-ethyl; 2-phenyl-ethyl; isopropyl; 2-phenylpropyl; 3- phenylpropyl; 3-phenoxy-propyl; 3- (1H-indol-3-yl) -propyl; 4-methoxy phenyl; 4- fluoro-phenyl; 4- benzyloxy-3-methoxy-phenyl; isobutyl; 5-cyclohexyl; octyl; benzyl; pyridin-2-yl; pyridin-yl; thiophen-3-yl; benzylsulfanyl and 2-phenylmethanesulfanyl. 11) The compound according to claim 1, characterized in that: the compound is selected from compounds and their pharmaceutically acceptable salts selected from the group consisting of N-hydroxy-3- [l- (3-hydroxy-propyl) -2- (2-phenyl-propyl) -lH-benzimidazol-5-yl] -acrylamide $ OH N-hydroxy-3- [l- (3,4,5-trimethoxybenzyl) -2- (2-phenyl-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (4-benzyloxy-3-methoxy-phenyl) -l-methyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (4-benzyloxy-3-methoxy-phenyl) -l- (3-hydroxy-propyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2-hydroxy-ethyl) -2- (4-methoxy-phenyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2,3 -hydroxy-propyl) -2- (4-methoxy-phenyl) -l H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (4-benzyloxy-3-methoxy-phenyl) -l- (2,3-hydroxy-? Yl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2,3-hydroxy-propyl) -2- (2-phenyl-ethyl) -l H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2,3-hydroxy-propyl) -2- (2-pyridyl) -l H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2-hydroxy-ethyl) -2- (4-pyridyl) -1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy) ? ropil) -2- (4-pyridyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-pyridylmethyl) -2- (2-phenyl-ethyl) -1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2- (2-pyridyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2-phenethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-methoxy-propyl) -2-phenethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (2-phenethyl-1- (pyridin-2-yl) methyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [l- (3-dimethylamino-2,2- dimethyl-? ropil) -2-phenethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-phenethyl-1- (2-pyridin-2-yl-ethyl-1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-benzyloxymethyl-1- (3-hydroxy-propyl-1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2-thiophen-3-yl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2- isobutyl-1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-isobutyl-1- (2-pyridin- 2- yl-ethyl) - 1 H-benzimidazol-5-yl] - acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2- octyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy- [2-cyclohexyl-l- (3-hydroxypropyl) -l H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (2-isobutyl-l-phenethyl-lH-benzimidazole-5 -yl] -acrylamide N-hydroxy-3- (1, 2-diphenylethyl-1H-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [2-phenethyl-1- (2-pyridin-3-yl-ethyl-O-benzimidazole- 5-yl] - acrylamide N-hydroxy-3- [2-benzyloxymethyl-1- (2-pyridin-3-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-hydroxy-propyl) -2- isobutyl-lH-benzimidazol-5-yl] -propionamide N-hydroxy-3-. { l- [3- (2-Oxo-pinolidin-1-yl) -α-ro-pyl] -2-phenethyl-1H-benzimidazol-5-yl} -acylamide 3_ [5_ (2_hydrocarbamoyl-vinyl) -2- phenethyl-lH-benzimidazol-1-yl] -propionic acid N-hydroxy-3- (l-benzyl-2-phenethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (l-benzyl-2-isobutyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (1-benzyl-1 H-benzimidazol-5-yl) -acylamide N-hydroxy-3- (2-phenethyl-l-propyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (l-propyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (l-etii-2-phenethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (l-ethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxA3- [2- (2-phenyl-propu) -l- (2-pyridin-3-yl-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2-pyridin-2-yl-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (l-ethyl-2-methyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2-morpholin-4-yl-ethyl-2-phenethyl-1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-phenethyl-1- (3, 4,5-trimethoxy-benzyl) -! H -benzimidazol-5-yl] -propionamide. N-hydroxy-3- [l- (3-hydroxy-pro? Il) -2- isopropyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (l-methyl-2-phenethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (1-methyl-1 H-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (2-phenethyl-lH-benzimidazol-5-yl) -acylamide N-hydroxy-3- (1 H-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [l-methyl-2- (3-phenyl-propyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (l, 2-dimethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [l-methyl-2- (phenylacetylamino-methyl) -lH-benzimidazol-5-yl] -acrylamide N- [5- (2-hydroxycarbomethyl-vinyl) -l-methyl-1 H-benzimidazol-2-ylmethyl] -isonicotinamide N-hydroxy-3- [l- (3-imidazol-l-yl-propyl) -2-phenethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (4-dimethylamino-butyl) -2-phenethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (3-benzyl) -2-phenethyl-3H- benzimidazol-5-yl] -acrylamide N-hydroxy-3- (3-methyl-2-phenethyl-3H-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [2- (benzylamino-methyl) -l-methyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3-. { 2 - [(dibenzylamino) -methyl] -1-methyl-1 H-benzimidazol-5-yl} - acrylamide N-hydroxy-3-. { 2 - [(4-methoxy-benzylamino) -methyl] -l-methyl-1H-benzimidazol-5-yl} -acylamide N-hydroxy-3- [l- (3-dimethylamino-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (benzylamino-methyl) -ethyl-1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (2- (benzyl-l-methyl-3-oxo-1 H-benzimidazol-5-yl) -acrylamide N-hydroxy-3- [l- (2-diethylamino-ethyl) -2-phenethyl-1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-phenethyl-1- (piperidin-1-yl-ethyl) -1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3-. { 2 - [(dibenzylamino) -methyl] -1-ethyl-1 H-benzimidazol-5-yl} -acylamide N-hydroxy-3- (2- { [2- (4-fluoro-phenyl) -acetylamino] -methyl].-L-methyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3 - [l-Ethyl-2- (2-phenylacetylamino-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (2-benzenesulfonylamino-ethyl) -l-ethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2-phenethyl-1- (2-pyrrolidin-1-yl-ethyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3-. { l-ethyl-2- [2- (2-phenoxy-acetylamino) -ethyl] -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [2- (2-benzylamino-ethyl) -L ethyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2,2-dimethyl-propyl) -2-phenethyl-1 H-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (l-benzyl-? I? Eridin-4-yl) -2-phenethyl-lH-benzimidazol-5-yl] acrylamide N-hydroxy-3- [l- (2-hydroxyethyl) -2-phenethyl-1 H-benzimidazol-5-yl] -acrylamide 10 N-hydroxy-3- [l- (5-hydroxy-pentyl) -2-fentyl-1 H-benzimidazol-5-yl] -acrylamide 15 N-hydroxy-3- (l-allyl-2-phenethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3- (1- (3-isoproxy-propyl) -2-20-phenethyl-1H-benzimidazol-5-yl) -acrylamide N-hydroxy-3-. { l- [3- (4-Methyl-pi? erazin-l-yl) -2-phenethyl] -lH-benzimidazol-5-yl} - acrylamide N-hydroxy-3- [2-phenethyl-1- (3-pyrrolidin-1-yl-propyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-dimethylamino-2,2-dimethyl-propyl) -2- (3-phenyl-propyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3-. { l- (3-Dimethylamino-2,2-dimethyl-propyl) -2- [2- (4-fluoro-phenyl) -ethyl] -1H-benzimidazol-5-yl] -acrylamide N-hydroxy-3-. { 2- (4-Fluoro-phenyl) -ethyl]-AA OH lH-benzimidazol-5-yl} - acrylamide H N-hydroxy-3- [l- (3-dimethylamino-2,2-dimethyl-ylpyl) -2- (2-pyridin-3-yl-ethyl) - lH-benzimidazol-5-yl] - acrylamide N-hydroxy-3- [2- (2-pyridin-3-yl-propyl) - lH-benzimidazol-5-yl] -acrylamide 2- [2-phenethyl-1- (3,4,5-trimethoxy-benzyl) -lH-benzimidazol-5-yl] -cyclopropanecarboxylic acid hydroxyamide N-hydroxy-3- [2-benzylsulfanyl-1- (3-dimethylamino-2-2, dimethyl-propyl) -lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (2-piperidin-l-yl-ethyl) - lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- [l- (3-dimethylamino-2,2-dimethyl-pro? Il) -2-phenylmethanesulfonyl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (2-benzyl-l-ethyl-lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3-. { l-ethyl-2- [3- (lH-indol-3-yl) -propyl] -lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3-. { l- (3-Dimethylamino-2,2-dimethyl-propyl) -2- [2- (3-methoxy-phenyl) -ethyl] -lH-benzimidazol-5-yl) -acrylamide N-hydroxy-3-. { 2- (3-methoxy-phenyl) -ethyl] -1 H-benzimidazol-5-yl} -acylamide N-hydroxy-3- [l-ethyl-2- (3-phenoxy-propyl) -1 H-benzimidazol-5- 1] -acrylamide (L) -N-hydroxy-3- [2- (l-amino- 2-phenyl-ethyl-O-methyl-lH-benzimidazol-5-ü] -acrylamide N-hydroxy-3- (3-oxy-2-pyridin-2-yl-lH-benzimidazol-5-yl] -acrylamide N-hydroxy-3- (2- { [2- (4-methoxy-fenü) -acetylamm] -methyl} - l-methyl-lH-benzimidazol-5-yl) -acrylamide

2- (l-Methyl-2-phenethyl-lH-benzimidazol-5-yl) -cyclopropanecarboxylic acid hydroxyamide 12) A pharmaceutical composition characterized in that it includes a compound according to any of claims 1 to 11 and a pharmaceutically acceptable diluent, excipient or carrier. 13) Use of a compound according to any of claims 1 to 11 in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis. 14) A use according to claim 13, characterized in that the disorder is a proliferative disorder. 15) A use according to claim 14, characterized in that the proliferative disorder is cancer. 16) A method for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis in a patient, characterized in that it includes the 5 administration of a therapeutically effective amount of a compound according to any of claims 1 to 11 to the patient. 17) A method according to claim 16, characterized in that the disorder is a proliferative disorder. 18) A method according to claim 16, characterized in that the disorder is cancer. 19) Use of a compound according to any of claims 1 to 11 or a pharmaceutical composition according to claim 12 to modify the activity of deacetylase. 20) A use according to claim 19, characterized in that the activity of deacetylase is the activity of histone deacetylase. 21) A use according to claim 19, characterized in that the activity of deacetylase is the activity of histone deacetylase class I. 22) Use according to claim 20 or 21, characterized or because histone deacetylase is HDAC 1. 23) A use according to claim 20 or 21, characterized in that the histone deacetylase is HDAC8. 24) A method of treating a disorder that can be treated by inhibiting histone deacetylase in a patient, which includes administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 11. . 25) A method according to claim 24, characterized in that the disorder is selected from the group consisting of antiproliferative disorders (eg, cancer); neurodegenerative diseases such as Huntington's disease, polyglutamine disease, Parkinson's disease, Alzheimer's disease, seizures, nigrostriatal degeneration, progressive supranuclear palsy, torsional dystonia, spasmodic torticollis and dyskinesia, familial tremor, Gilles de la Tourette syndrome, diffuse disease by Lewy bodies, progressive supranuclear palsy, Pick's disease, intracerebral hemongia, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy's syndrome Drager; metabolic diseases including type 2 diabetes; degenerative diseases of the eye, including glaucoma, macular degeneration associated with age, rubella glaucoma; inflammatory diseases and / or disorders of the immune system, including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis, diabetes, Sjoegren's syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; disease including angiogenesis, for example cancer, psoriasis, rheumatoid arthritis; psychological disorders that include bipolar illness, schizophrenia, mania, depression and dementia; cardiovascular diseases such as heart failure, restenosis and arteriosclerosis; fibrotic diseases such as hepatic fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example by Candida Albicans, bacterial infections, viral infections, for example herpes simplex, protozoal infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis, and hematopoietic disorders such as , for example thalassemia, anemia and sickle cell anemia. 26) A method for inhibiting cell proliferation that includes the administration of an effective amount of a compound according to any of claims 1 to 11. 27) A method for the treatment of a neurodegenerative disorder in a patient, including administration the patient of a therapeutically effective amount of a compound according to any one of claims 1 to 11. 28) A method according to claim 27, characterized in that the neurodegenerative disorder is Huntington's disease. 29) A method of treating an inflammatory disease and / or a disorder of the immune system in a patient, including administering to the patient a therapeutically effective amount of a compound according to any of claims 1 to 11. 30) A method according to claim 29, characterized in that the inflammatory disease and / or the immune system disorder is rheumatoid arthritis. 31) A method according to claim 29, characterized in that the inflammatory disease and / or the immune system disorder is systemic lupus erythematosus. 32) A method for measuring the concentration of an acetylated histone in a biological sample by an enzyme-linked immunosorbent assay, wherein the enzyme-linked immunosorbent assay includes a combination of a primary capture antibody, or a portion thereof, and a secondary detection antibody, or a portion thereof. 33) A method according to claim 32, characterized in that the primary capture antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, an acetylated polyclonal anti-H3 antibody, a polyclonal goat anti-H3 antibody, a goat polyclonal anti-H3 antibody and one of its combinations. 34) A method according to claim 32 or 33, characterized in that the secondary detection antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, xm acetylated polyclonal anti-H3 antibody, a polyclonal goat anti-H3 antibody , a goat acetylated polyclonal anti-H3 antibody and one of its combinations. 35) A method according to claim 32, characterized in that the primary capture antibody is a mouse anti-H3 monoclonal antibody and the secondary detection antibody is a rat acetylated anti-H3 polyclonal antibody. 36) A method for identifying the pharmacological effect of a histone deacetylase inhibitor in a cell, which includes the steps of: a) providing a cell that has been treated with a histone deacetylase inhibitor; b) measuring the concentration of acetylated histone in the cell by a method according to any of claims 32 to 35; Y 5 c) compare the concentration of acetylated histone with the concentration of acetylated histone in a control sample. 37) A method according to claim 36, characterized in that the control sample is derived from a cell that has not been treated with a histone deacetylase inhibitor. 0 38) A method according to claim 36 or 37, characterized in that the cell is a tumor cell. 39) A method for identifying the pharmacological effect of a histone deacetylase inhibitor in a subject, which includes the steps of: a) obtaining a biological sample from a subject that has been treated with a histone deacetylase inhibitor; b) measuring the concentration of acetylated histone in the biological sample by a method according to any of claims 32 to 35; and c) comparing the concentration of acetylated histone with the concentration or acetylated histone of the control sample. 40) A method according to claim 39, characterized in that the control sample is a biological sample derived from a subject that has not been treated with a histone deacetylase inhibitor. 41) A method according to either of. claims 32 to 35 or 39 to 40. characterized in that the biological sample is selected from the group consisting of tissue, blood, serum, plasma, urine, saliva and a combination thereof. 42) A method according to claim 36 or claim 37, characterized in that the histone deacetylase inhibitor includes a compound according to any of claims 1 to 11.